A multivariate neuroimaging biomarker of individual outcome to transcranial magnetic stimulation in depression.

The neurobiology of major depressive disorder (MDD) remains incompletely understood, and many individuals fail to respond to standard treatments. Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (DLPFC) has emerged as a promising antidepressant therapy. However, the heterogeneity of response underscores a pressing need for biomarkers of treatment outcome. We acquired resting state functional magnetic resonance imaging (rsfMRI) data in 47 MDD individuals prior to 5-8 weeks of rTMS treatment targeted using the F3 beam approach and in 29 healthy comparison subjects. The caudate, prefrontal cortex, and thalamus showed significantly lower blood oxygenation level-dependent (BOLD) signal power in MDD individuals at baseline. Critically, individuals who responded best to treatment were associated with lower pre-treatment BOLD power in these regions. Additionally, functional connectivity (FC) in the default mode and affective networks was associated with treatment response. We leveraged these findings to train support vector machines (SVMs) to predict individual treatment responses, based on learned patterns of baseline FC, BOLD signal power and clinical features. Treatment response (responder vs. nonresponder) was predicted with 85-95% accuracy. Reduction in symptoms was predicted to within a mean error of ±16% (r = .68, p < .001). These preliminary findings suggest that therapeutic outcome to DLPFC-rTMS could be predicted at a clinically meaningful level using only a small number of core neurobiological features of MDD, warranting prospective testing to ascertain generalizability. This provides a novel, transparent and physiologically plausible multivariate approach for classification of individual response to what has become the most commonly employed rTMS treatment worldwide. This study utilizes data from a larger clinical study (Australian New Zealand Clinical Trials Registry: Investigating Predictors of Response to Transcranial Magnetic Stimulation for the Treatment of Depression; ACTRN12610001071011; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=336262).

Occipital bending in schizophrenia.

OBJECTIVE: To investigate the prevalence of occipital bending (an occipital lobe crossing or twisting across the midline) in subjects with schizophrenia and matched healthy controls. METHOD: Occipital bending prevalence was investigated in 37 patients with schizophrenia and 44 healthy controls. RESULTS: Ratings showed that prevalence was nearly three times higher among schizophrenia patients (13/37 [35.1%]) than in control subjects (6/44 [13.6%]). Furthermore, those with schizophrenia had greater normalized gray matter volume but less white matter volume and had larger brain-to-cranial ratio. CONCLUSION: The results suggest that occipital bending is more prevalent among schizophrenia patients than healthy subjects and that schizophrenia patients have different gray matter-white matter proportions. Although the cause and clinical ramifications of occipital bending are unclear, the results infer that occipital bending may be a marker of psychiatric illness.

A STUDY OF THE PATTERN OF RESPONSE TO rTMS TREATMENT IN DEPRESSION.

BACKGROUND: Considerable research has demonstrated the efficacy of repetitive transcranial magnetic stimulation (rTMS) treatment in patients with depression. However, limited research has described the pattern of response to rTMS treatment or explored possible predictors of the likelihood of treatment response. METHODS: Data from 11 clinical trials (n = 1,132) was pooled and we described the pattern of response to rTMS, rate of response, and remission as well as potential clinical and demographic predictors of response. RESULTS: There was a bimodal pattern of response to rTMS with the response-associated peak at 57% reduction in depression rating scale scores. About 46% of patients achieved response criteria, with 31% completing rTMS treatment in remission. A greater likelihood of response was seen for patients who had less severe depression at baseline, a shorter duration of the current episode, and recurrent rather than single episode of depression. Greater response was also seen in patients treated at higher stimulation intensity. CONCLUSIONS: A meaningful percentage (>40%) of patients respond to a course of rTMS treatment. Response does vary with a number of clinical and demographic variables but none of these variables exert a sufficiently strong influence on response rates to warrant using these criteria to exclude patients from treatment.

Equal Improvement in Men and Women in the Treatment of Urologic Chronic Pelvic Pain Syndrome Using a Multi-modal Protocol with an Internal Myofascial Trigger Point Wand.

Both men and women require treatment for urologic chronic pelvic pain syndromes (UCPPS), which includes interstitial cystitis/painful bladder syndrome, pelvic floor dysfunction, and chronic prostatitis/chronic pelvic pain syndrome. However, it is unknown if men and women respond differently to a protocol that includes specific physical therapy self-treatment using an internal trigger point wand and training in paradoxical relaxation. We performed a retrospective analysis by gender in a single arm, open label, single center clinical trial designed to evaluate the safety and effectiveness of a protocol for the treatment of UCPPS from October, 2008 to May, 2011. 314 adult men (79.9 %) and 79 (20.1 %) women met inclusion criteria. The median duration of symptoms was 60 months. The protocol required an initial 6-day clinic for training followed by a 6-month self-treatment period. The treatment included self-administered pelvic floor trigger point release with an internal trigger point device for physical therapy along with paradoxical relaxation training. Notable gender differences in prior treatments were observed. Men had a lower median [Interquartile Range] NIH-CPSI score at baseline than women (27 [21, 31] vs. 29 [22, 33], p = 0.04). Using a 1-10 scale with 10 = Most Severe, the median reduction in trigger point sensitivity was 3 units for both men and women after 6 months therapy (p = 0.74). A modified Intention to Treat analysis and a multivariate regression analysis found similar results. We conclude that men and women have similar, significant reductions in trigger point sensitivity with this protocol.

Occipital bending in depression.

There are reports of differences in occipital lobe asymmetry within psychiatric populations when compared with healthy control subjects. Anecdotal evidence and enlarged lateral ventricles suggests that there may also be a different pattern of curvature whereby one occipital lobe wraps around the other, termed 'occipital bending'. We investigated the prevalence of occipital bending in 51 patients with major depressive disorder (males mean age = 41.96 ± 14.00 years, females mean age = 40.71 ± 12.41 years) and 48 age- and sex-matched healthy control subjects (males mean age = 40.29 ± 10.23 years, females mean age = 42.47 ± 14.25 years) and found the prevalence to be three times higher among patients with major depressive disorder (18/51, 35.3%) when compared with control subjects (6/48, 12.5%). The results suggest that occipital bending is more common among patients with major depressive disorder than healthy subjects, and that occipital asymmetry and occipital bending are separate phenomena. Incomplete neural pruning may lead to the cranial space available for brain growth being restricted, or ventricular enlargement may exacerbate the natural occipital curvature patterns, subsequently causing the brain to become squashed and forced to 'wrap' around the other occipital lobe. Although the clinical implications of these results are unclear, they provide an impetus for further research into the relevance of occipital bending in major depression disorder.

Chronic pelvic pain syndrome: reduction of medication use after pelvic floor physical therapy with an internal myofascial trigger point wand.

This study documents the voluntary reduction in medication use in patients with refractory chronic pelvic pain syndrome utilizing a protocol of pelvic floor myofascial trigger point release with an FDA approved internal trigger point wand and paradoxical relaxation therapy. Self-referred patients were enrolled in a 6-day training clinic from October, 2008 to May, 2011 and followed the protocol for 6 months. Medication usage and symptom scores on a 1-10 scale (10 = most severe) were collected at baseline, and 1 and 6 months. All changes in medication use were at the patient's discretion. Changes in medication use were assessed by McNemar's test in both complete case and modified intention to treat (mITT) analyses. 374 out of 396 patients met inclusion criteria; 79.7 % were male, median age of 43 years and median symptom duration of 5 years. In the complete case analysis, the percent of patients using medications at baseline was 63.6 %. After 6 months of treatment the percentage was 40.1 %, a 36.9 % reduction (p < 0.001). In the mITT analysis, there was a 22.7 % overall reduction from baseline (p < 0.001). Medication cessation at 6 months was significantly associated with a reduction in total symptoms (p = 0.03).

Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes.

PURPOSE: We determined the feasibility of conducting a randomized clinical trial designed to compare 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) in patients with urological chronic pelvic pain syndromes. MATERIALS AND METHODS: We recruited 48 subjects with chronic prostatitis/chronic pelvic pain syndrome or interstitial cystitis/painful bladder syndrome at 6 clinical centers. Eligible patients were randomized to myofascial physical therapy or global therapeutic massage and were scheduled to receive up to 10 weekly treatments of 1 hour each. Criteria to assess feasibility included adherence of therapists to prescribed therapeutic protocol as determined by records of treatment, adverse events during study treatment and rate of response to therapy as assessed by the patient global response assessment. Primary outcome analysis compared response rates between treatment arms using Mantel-Haenszel methods. RESULTS: There were 23 (49%) men and 24 (51%) women randomized during a 6-month period. Of the patients 24 (51%) were randomized to global therapeutic massage, 23 (49%) to myofascial physical therapy and 44 (94%) completed the study. Therapist adherence to the treatment protocols was excellent. The global response assessment response rate of 57% in the myofascial physical therapy group was significantly higher than the rate of 21% in the global therapeutic massage treatment group (p = 0.03). CONCLUSIONS: We judged the feasibility of conducting a full-scale trial of physical therapy methods and the preliminary findings of a beneficial effect of myofascial physical therapy warrants further study.

Alfuzosin and symptoms of chronic prostatitis-chronic pelvic pain syndrome.

BACKGROUND: In men with chronic prostatitis-chronic pelvic pain syndrome, treatment with alpha-adrenergic receptor blockers early in the course of the disorder has been reported to be effective in some, but not all, relatively small randomized trials. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy of alfuzosin, an alpha-adrenergic receptor blocker, in reducing symptoms in men with chronic prostatitis-chronic pelvic pain syndrome. Participation in the study required diagnosis of the condition within the preceding 2 years and no previous treatment with an alpha-adrenergic receptor blocker. Men were randomly assigned to treatment for 12 weeks with either 10 mg of alfuzosin per day or placebo. The primary outcome was a reduction of at least 4 points (from baseline to 12 weeks) in the score on the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (range, 0 to 43; higher scores indicate more severe symptoms). A 4-point decrease is the minimal clinically significant difference in the score. RESULTS: A total of 272 eligible participants underwent randomization, and in both study groups, 49.3% of participants had a decrease of at least 4 points in their total NIH-CPSI score (rate difference associated with alfuzosin, 0.1%; 95% confidence interval, -11.2 to 11.0; P=0.99). In addition, a global response assessment showed similar response rates at 12 weeks: 33.6% in the placebo group and 34.8% in the alfuzosin group (P=0.90). The rates of adverse events in the two groups were also similar. CONCLUSIONS: Our findings do not support the use of alfuzosin to reduce the symptoms of chronic prostatitis-chronic pelvic pain syndrome in men who have not received prior treatment with an alpha-blocker. (ClinicalTrials.gov number, NCT00103402.)

Sacral nerve stimulator revision due to somatic growth.

PURPOSE: Sacral nerve modulation is a Food and Drug Administration approved treatment for refractory urgency, frequency, urge incontinence and nonobstructive urinary retention in adults. The sparse literature on sacral nerve modulation in children focuses on its initial efficacy in patients with neurogenic bladder and dysfunctional elimination. We describe our initial experience with sacral nerve modulation and the phenomenon of growth spurts associated with lead malfunction that necessitates revision. MATERIALS AND METHODS: After receiving institutional review board approval we retrospectively reviewed the charts of pediatric patients who underwent sacral nerve modulation surgery at our institution. Charts were examined for patient demographics, subjective success, the need for further surgery and success after revision. RESULTS: Four patients underwent sacral nerve modulation at an average age of 12.1 years. All patients reported initial success, defined as greater than 50% symptom improvement. Subsequently 3 patients required a total of 5 revisions due to lead malfunction with an average of 1.5 years between surgeries. In those requiring revision the average somatic growth between revisions was 8.1 cm. Return of efficacy was reported after each revision. All patients had functioning nerve stimulators in place and continued to have a positive subjective response. CONCLUSIONS: The sparse data on sacral nerve modulation in children shows efficacy and safety similar to those in adults. Somatic growth may be associated with lead malfunction and require surgical revision. We report a small series showing that revision can be done successfully and safely. Informed consent for sacral nerve modulation in pediatric patients should include a discussion of somatic growth as a possible cause of lead malfunction necessitating revision.

6-day intensive treatment protocol for refractory chronic prostatitis/chronic pelvic pain syndrome using myofascial release and paradoxical relaxation training.

PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome continues to elude conventional therapy. Evidence supports the concept that phenotypes of pelvic muscular tenderness and psychosocial distress respond to myofascial trigger point release and specific relaxation training. This case series reports long-term outcomes of a 6-day intensive combination of such therapies in refractory cases. MATERIALS AND METHODS: A total of 200 men with pain for a median of 4.8 years referred themselves to Stanford University Urology for participation in an established protocol. Daily 3 to 5-hour sessions including intrapelvic/extrapelvic physiotherapy, self-treatment training and paradoxical relaxation training provided a solid introduction to facilitate self-management. Subjects answered baseline and followup questionnaires at variable intervals after initiation of therapy including the National Institutes of Health Chronic Prostatitis Symptom Index, global response assessment and a psychological query. RESULTS: We followed 116 men for a median of 6 months. Baseline total symptom index was 26 out of a maximum 43 points. Scores decreased by 30% (p <0.001) at followup with 60% of subjects demonstrating a 6-point or greater decrease (range 6 to 30). Domains of pain, urinary dysfunction and quality of life showed significant improvement (p <0.001). Global response assessment revealed that 82% of subjects reported improvement (59% marked to moderate, 23% slight). CONCLUSIONS: Men with chronic pelvic pain refractory to traditional treatment benefit from intensive myofascial trigger point therapy and concomitant paradoxical relaxation training. Education in techniques for self-administered trigger point release and continued pelvic muscle relaxation help patients reduce pain and dysfunction. Refinement of clinical phenotyping and selection of patients with pelvic muscle tenderness should enhance the success rate with this treatment modality.

Exploring Transfers between Earth-Moon Halo Orbits via Multi-Objective Reinforcement Learning.

Multi-Reward Proximal Policy Optimization, a multi-objective deep reinforcement learning algorithm, is used to examine the design space of low-thrust trajectories for a SmallSat transferring between two libration point orbits in the Earth-Moon system. Using Multi-Reward Proximal Policy Optimization, multiple policies are simultaneously and efficiently trained on three distinct trajectory design scenarios. Each policy is trained to create a unique control scheme based on the trajectory design scenario and assigned reward function. Each reward function is defined using a set of objectives that are scaled via a unique combination of weights to balance guiding the spacecraft to the target mission orbit, incentivizing faster flight times, and penalizing propellant mass usage. Then, the policies are evaluated on the same set of perturbed initial conditions in each scenario to generate the propellant mass usage, flight time, and state discontinuities from a reference trajectory for each control scheme. The resulting low-thrust trajectories are used to examine a subset of the multi-objective trade space for the SmallSat trajectory design scenario. By autonomously constructing the solution space, insights into the required propellant mass, flight time, and transfer geometry are rapidly achieved.

Stress induced hypothalamus-pituitary-adrenal axis responses and disturbances in psychological profiles in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: Chronic pelvic pain in men has a strong relationship with biopsychosocial stress and central nervous system sensitization may incite or perpetuate the pain syndrome. We evaluated patients and asymptomatic controls for psychological factors and neuroendocrine reactivity under provoked acute stress conditions. MATERIALS AND METHODS: Men with pain (60) and asymptomatic controls (30) completed psychological questionnaires including the Perceived Stress, Beck Anxiety, Type A behavior and Brief Symptom Inventory for distress from symptoms. Hypothalamic-pituitary-adrenal axis function was measured during the Trier Social Stress Test with serum adrenocorticotropin hormone and cortisol reactivity at precise times, before and during acute stress, which consisted of a speech and mental arithmetic task in front of an audience. The Positive and Negative Affective Scale measured the state of emotions. RESULTS: Patients with chronic pelvic pain had significantly more anxiety, perceived stress and a higher profile of global distress in all Brief Symptom Inventory domains (p <0.001), scoring in the 94th vs the 49th percentile for controls (normal population). Patients showed a significantly blunted plasma adrenocorticotropin hormone response curve with a mean total response approximately 30% less vs controls (p = 0.038) but no differences in any cortisol responses. Patients with pelvic pain had less emotional negativity after the test than controls, suggesting differences in cognitive appraisal. CONCLUSIONS: Men with pelvic pain have significant disturbances in psychological profiles compared to healthy controls and evidence of altered hypothalamic-pituitary adrenal axis function in response to acute stress. These central nervous system observations may be a consequence of neuropsychological adjustments to chronic pain and modulated by personality.

Painful myofascial trigger points and pain sites in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: A combination of manual physiotherapy and specific relaxation training effectively treats patients with chronic prostatitis/chronic pelvic pain syndrome. However, little information exists on myofascial trigger points and specific chronic pelvic pain symptoms. We documented relationships between trigger point sites and pain symptoms in men with chronic prostatitis/chronic pelvic pain syndrome. MATERIALS AND METHODS: We randomly selected a cohort of 72 men who underwent treatment with physiotherapy and relaxation training from 2005 to 2008. Patients self-reported up to 7 pelvic pain sites before treatment and whether palpation of internal and external muscle trigger points reproduced the pain. Fisher's exact test was used to compare palpation responses, ie referral pain, stratified by reported pain site. RESULTS: Pain sensation at each anatomical site was reproduced by palpating at least 2 of 10 designated trigger points. Furthermore, 5 of 7 painful sites could be reproduced at least 50% of the time (p <0.05). The most prevalent pain sites were the penis in 90.3% of men, the perineum in 77.8% and the rectum in 70.8%. Puborectalis/pubococcygeus and rectus abdominis trigger points reproduced penile pain more than 75% of the time (p <0.01). External oblique muscle palpation elicited suprapubic, testicular and groin pain in at least 80% of the patients at the respective pain sites (p <0.01). CONCLUSIONS: This report shows relationships between myofascial trigger points and reported painful sites in men with chronic prostatitis/chronic pelvic pain syndrome. Identifying the site of clusters of trigger points inside and outside the pelvic floor may assist in understanding the role of muscles in this disorder and provide focused therapeutic approaches.

Randomized multicenter feasibility trial of myofascial physical therapy for the treatment of urological chronic pelvic pain syndromes.

PURPOSE: We determined the feasibility of conducting a randomized clinical trial designed to compare 2 methods of manual therapy (myofascial physical therapy and global therapeutic massage) in patients with urological chronic pelvic pain syndromes. MATERIALS AND METHODS: We recruited 48 subjects with chronic prostatitis/chronic pelvic pain syndrome or interstitial cystitis/painful bladder syndrome at 6 clinical centers. Eligible patients were randomized to myofascial physical therapy or global therapeutic massage and were scheduled to receive up to 10 weekly treatments of 1 hour each. Criteria to assess feasibility included adherence of therapists to prescribed therapeutic protocol as determined by records of treatment, adverse events during study treatment and rate of response to therapy as assessed by the patient global response assessment. Primary outcome analysis compared response rates between treatment arms using Mantel-Haenszel methods. RESULTS: There were 23 (49%) men and 24 (51%) women randomized during a 6-month period. Of the patients 24 (51%) were randomized to global therapeutic massage, 23 (49%) to myofascial physical therapy and 44 (94%) completed the study. Therapist adherence to the treatment protocols was excellent. The global response assessment response rate of 57% in the myofascial physical therapy group was significantly higher than the rate of 21% in the global therapeutic massage treatment group (p = 0.03). CONCLUSIONS: We judged the feasibility of conducting a full-scale trial of physical therapy methods and the preliminary findings of a beneficial effect of myofascial physical therapy warrants further study.

Psychometric profiles and hypothalamic-pituitary-adrenal axis function in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: Abnormal regulation of the hypothalamic-pituitary-adrenal axis and diurnal cortisol rhythms are associated with several pain and chronic inflammatory conditions. Chronic stress may have a role in the disorder of chronic prostatitis/chronic pelvic pain syndrome related to initiation or exacerbation of the syndrome. We tested the hypothesis that men with chronic pelvic pain syndrome have associated disturbances in psychosocial profiles and hypothalamic-pituitary-adrenal axis function. MATERIALS AND METHODS: A total of 45 men with chronic pelvic pain syndrome and 20 age matched, asymptomatic controls completed psychometric self-report questionnaires including the Type A personality test, Perceived Stress Scale, Beck Anxiety Inventory and Brief Symptom Inventory for distress from physical symptoms. Saliva samples were collected on 2 consecutive days at 9 specific times with strict reference to time of morning awakening for evaluation of free cortisol, reflecting secretory activity of the hypothalamic-pituitary-adrenal axis. We quantified cortisol variations as the 2-day average slope of the awakening cortisol response and the subsequent diurnal levels. RESULTS: Men with chronic pelvic pain syndrome had more perceived stress and anxiety than controls (p <0.001). Brief Symptom Index scores were significantly increased in all scales (somatization, obsessive/compulsive behavior, depression, anxiety, hostility, interpersonal sensitivity, phobic anxiety, paranoid ideation, psychoticism) for chronic pelvic pain syndrome, and Global Severity Index rank for chronic pelvic pain syndrome was 93rd vs 48th percentile for controls (p <0.0001). Men with chronic pelvic pain syndrome had significantly increased awakening cortisol responses, mean slope of 0.85 vs 0.59 for controls (p <0.05). CONCLUSIONS: Men with chronic pelvic pain syndrome scored exceedingly high on all psychosocial variables and showed evidence of dysfunctional hypothalamic-pituitary-adrenal axis function reflected in augmented awakening cortisol responses. Observations suggest variables in biopsychosocial interaction that suggest opportunities for neurophysiological study of relationships of stress and chronic pelvic pain syndrome.

Category III chronic prostatitis/chronic pelvic pain syndrome: insights from the National Institutes of Health Chronic Prostatitis Collaborative Research Network studies.

Chronic prostatitis/chronic pelvic pain syndrome remains an enigmatic medical condition. Creation of the National Institutes of Health-funded Chronic Prostatitis Collaborative Research Network (CPCRN) has stimulated a renewed interest in research on and clinical aspects of chronic prostatitis/chronic pelvic pain syndrome. Landmark publications of the CPCRN document a decade of progress. Insights from these CPCRN studies have improved our management of chronic prostatitis/chronic pelvic pain syndrome and offer hope for continued progress.

Chronic Prostatitis and/or Chronic Pelvic Pain as a Psychoneuromuscular Disorder-A Meta-analysis.

OBJECTIVE: To evaluate effectiveness of physical therapy, biofeedback, and/or cognitive behavioral therapy for chronic prostatitis/chronic pelvic pain syndrome (CP and/or CPPS). This symptom complex has resisted resolution from conventional urologic treatment of the prostate, which includes antibiotics, alpha-blockers, and analgesics. Beginning in 1995, a new paradigm was introduced viewing CP and/or CPPS as a psychoneuromuscular disorder driven by protective pelvic floor guarding and psychosocial stress. METHODS: A literature search (PubMed, Google Scholar, and the Cochran Library) was conducted from inception through December 2017 using key words related to CP and/or CPPS (eg, prostatitis and pelvic pain) with physical therapy (eg, myofascial trigger point release) and/or biofeedback or cognitive behavioral treatment. Studies were required to include pre- and post-treatment with the National Institutes of Health Chronic Prostatitis Symptom Index (CPSI) scores. RESULTS: Eight studies inclusive of 280 patients met primary inclusion criteria. Study sample sizes ranged from 8 to 116 men (mean = 35); treatment duration ranged from 8 to 26 weeks (mean = 14). Pretreatment mean CPSI scores ranged from 21.7 to 33.5. The nonstandardized weighted mean reduction of CPSI score from baseline was 8.8 points; 95% confidence interval (7.5, 11.1); P <.001. The I2 statistic = 18.5% indicating little heterogeneity between studies. A sensitivity analysis including an additional multimodal intervention study of with 100 patients produced similar findings. CONCLUSION: Conventional medical treatment often fails to resolve CP and/or CPPS. A 6-point reduction in CPSI score is considered a clinically meaningful improvement of symptoms. This meta-analysis shows that treating CP and/or CPPS as a psychoneuromuscular disorder can significantly exceed this clinical threshold.

Repetitive transcranial magnetic stimulation for treatment resistant depression: Re-establishing connections.

Repetitive transcranial magnetic stimulation (rTMS) is a relatively recent addition to the neurostimulation armamentarium for treating individuals suffering from treatment refractory depression and has demonstrated efficacy in clinical trials. One of the proposed mechanisms of action underlying the therapeutic effects of rTMS for depression involves the modulation of depression-associated dysfunctional activity in distributed brain networks involving frontal cortical and subcortical limbic regions, via changes to aberrant functional and structural connectivity. Although there is currently a paucity of published data, we review changes to functional and structural connectivity following rTMS for depression. Current evidence suggests an rTMS-induced normalisation of depression-associated dysfunction within and between large scale functional networks, including the default mode, central executive and salience networks, associated with an amelioration of depressive symptoms. Additionally, changes to measures of white matter microstructure, primarily in the dorsolateral prefrontal cortex, have also been reported following rTMS for depression, possibly reversing depression-associated abnormalities. We argue that measures of functional and structural connectivity can be used to optimise rTMS targeting within the dorsolateral prefrontal cortex and also to explore novel rTMS targets for depression. Finally, we discuss the utility of measures of brain connectivity as predictive biomarkers of rTMS treatment response in guiding therapeutic decisions.

Evaluation of an antiretroviral medication attitude scale and relationships between medication attitudes and medication nonadherence.

The objectives of this study were to refine a scale designed to assess attitudes toward antiretroviral medication, to examine variation in medication attitudes across clinical and demographic characteristics, and to assess relationships between medication attitudes and medication nonadherence. A cross-sectional design was used to survey individuals at least 18 years of age, currently on antiretroviral therapy, and served by a regional HIV/AIDS center. The survey was administered by pharmacy students using convenience sampling between February 2002 and August 2002. Nonadherence was measured using a nine-item scale with a higher score indicative of higher nonadherence. An antiretroviral medication attitude scale was developed based on revision of a zidovudine attitude inventory. The sample of 99 patients was predominantly male (79.8%), had an annual income of less than $10,000 (74%), and was comprised of 50% whites and 40.8% blacks. Participants were between 18 and 70 years old. Item reduction using item-total correlations and factor analytic techniques resulted in a 15-item medication attitude scale with good internal consistency (Cronbach alpha coefficient = 0.84). A multiple regression model showed a significant negative relationship between attitude toward medication and medication nonadherence after controlling for covariates including age, education, gender, ethnicity, work status, social support, CD4 cell count and number of antiretroviral medications, suggesting that more positive the attitude toward medication, lower the medication nonadherence. Findings underscore the importance of attitude toward medication as a modifiable factor that can be targeted to improve medication adherence.