TAZ/YAP fusion proteins: mechanistic insights and therapeutic opportunities.

The Hippo pathway is dysregulated in many different cancers, but point mutations in the pathway are rare. Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) fusion proteins have emerged in almost all major cancer types and represent the most common genetic mechanism by which the two transcriptional co-activators are activated. Given that the N termini of TAZ or YAP are fused to the C terminus of another transcriptional regulator, the resultant fusion proteins hyperactivate a TEAD transcription factor-based transcriptome. Recent advances show that the C-terminal fusion partners confer oncogenic properties to TAZ/YAP fusion proteins by recruiting epigenetic modifiers that promote a hybrid TEAD-based transcriptome. Elucidating these cooperating epigenetic complexes represents a strategy to identify new therapeutic approaches for a pathway that has been recalcitrant to medical therapy.

Mongooses (Urva auropunctata) as reservoir hosts of Leptospira species in the United States Virgin Islands, 2019-2020.

During 2019-2020, the Virgin Islands Department of Health investigated potential animal reservoirs of Leptospira spp., the bacteria that cause leptospirosis. In this cross-sectional study, we investigated Leptospira spp. exposure and carriage in the small Indian mongoose (Urva auropunctata, syn: Herpestes auropunctatus), an invasive animal species. This study was conducted across the three main islands of the U.S. Virgin Islands (USVI), which are St. Croix, St. Thomas, and St. John. We used the microscopic agglutination test (MAT), fluorescent antibody test (FAT), real-time polymerase chain reaction (lipl32 rt-PCR), and bacterial culture to evaluate serum and kidney specimens and compared the sensitivity, specificity, positive predictive value, and negative predictive value of these laboratory methods. Mongooses (n = 274) were live-trapped at 31 field sites in ten regions across USVI and humanely euthanized for Leptospira spp. testing. Bacterial isolates were sequenced and evaluated for species and phylogenetic analysis using the ppk gene. Anti-Leptospira spp. antibodies were detected in 34% (87/256) of mongooses. Reactions were observed with the following serogroups: Sejroe, Icterohaemorrhagiae, Pyrogenes, Mini, Cynopteri, Australis, Hebdomadis, Autumnalis, Mankarso, Pomona, and Ballum. Of the kidney specimens examined, 5.8% (16/270) were FAT-positive, 10% (27/274) were culture-positive, and 12.4% (34/274) were positive by rt-PCR. Of the Leptospira spp. isolated from mongooses, 25 were L. borgpetersenii, one was L. interrogans, and one was L. kirschneri. Positive predictive values of FAT and rt-PCR testing for predicting successful isolation of Leptospira by culture were 88% and 65%, respectively. The isolation and identification of Leptospira spp. in mongooses highlights the potential role of mongooses as a wildlife reservoir of leptospirosis; mongooses could be a source of Leptospira spp. infections for other wildlife, domestic animals, and humans.

Determination of freedom-from-rabies for small Indian mongoose populations in the United States Virgin Islands, 2019-2020.

Mongooses, a nonnative species, are a known reservoir of rabies virus in the Caribbean region. A cross-sectional study of mongooses at 41 field sites on the US Virgin Islands of St. Croix, St. John, and St. Thomas captured 312 mongooses (32% capture rate). We determined the absence of rabies virus by antigen testing and rabies virus exposure by antibody testing in mongoose populations on all three islands. USVI is the first Caribbean state to determine freedom-from-rabies for its mongoose populations with a scientifically-led robust cross-sectional study. Ongoing surveillance activities will determine if other domestic and wildlife populations in USVI are rabies-free.

TAZ-CAMTA1 and YAP-TFE3 alter the TAZ/YAP transcriptome by recruiting the ATAC histone acetyltransferase complex.

Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma that metastasizes early in its clinical course and lacks an effective medical therapy. The TAZ-CAMTA1 and YAP-TFE3 fusion proteins are chimeric transcription factors and initiating oncogenic drivers of EHE. A combined proteomic/genetic screen in human cell lines identified YEATS2 and ZZZ3, components of the Ada2a-containing histone acetyltransferase (ATAC) complex, as key interactors of both fusion proteins despite the dissimilarity of the C terminal fusion partners CAMTA1 and TFE3. Integrative next-generation sequencing approaches in human and murine cell lines showed that the fusion proteins drive a unique transcriptome by simultaneously hyperactivating a TEAD-based transcriptional program and modulating the chromatin environment via interaction with the ATAC complex. Interaction of the ATAC complex with both fusion proteins indicates that it is a key oncogenic driver and unifying enzymatic therapeutic target for this sarcoma. This study presents an approach to mechanistically dissect how chimeric transcription factors drive the formation of human cancers.

The proliferation of human cells is tightly regulated to ensure that enough cells are made to build and repair organs and tissues, while at the same time stopping cells from dividing uncontrollably and damaging the body. To get the right balance, cells rely on physical and chemical cues from their environment that trigger the biochemical signals that regulate two proteins called TAZ and YAP. These proteins control gene activity by regulating the rate at which genes are copied to produce proteins. If this process becomes dysregulated, cells can grow uncontrollably, causing cancer. In cancer cells, it is common to find TAZ and YAP fused to other proteins. In epithelioid hemangioendothelioma, a rare cancer that grows in the blood vessels, cancerous growth can be driven by a version of TAZ fused to the protein CAMTA1, or a version of YAP fused to the protein TFE3. While the role of TAZ and YAP in promoting gene activity is known, it is unclear how CAMTA1 and TFE3 contribute to cell growth becoming dysregulated. Merritt, Garcia et al. studied sarcoma cell lines to show that these two fusion proteins, TAZ-CAMTA1 and YAP-TFE3, change the pattern of gene activity seen in the cells compared to TAZ or YAP alone. An analysis of molecules that interact with the two fusion proteins identified a complex called ATAC as the cause of these changes. This complex adds chemical markers to DNA-packaging proteins, which control which genes are available for activation. The fusion proteins combine the ability of TAZ and YAP to control gene activity and the ability of CAMTA1 and TFE3 to make DNA more accessible, allowing the fusion proteins to drive uncontrolled cancerous growth. Similar TAZ and YAP fusion proteins have been found in other cancers, which can activate genes and potentially alter DNA packaging. Targeting drug development efforts at the proteins that complex with TAZ and YAP fusion proteins may lead to new therapies.

Photodynamic Therapy Using Hippo Pathway Inhibitor Verteporfin: A Potential Dual Mechanistic Approach in Treatment of Soft Tissue Sarcomas.

Sarcoma is a widely varied and devastating oncological subtype, with overall five-year survival of 65% that drops to 16% with the presence of metastatic disease at diagnosis. Standard of care for localized sarcomas is predicated on local control with wide-local resection and radiation therapy, or, less commonly, chemotherapy, depending on tumor subtype. Verteporfin has the potential to be incorporated into this standard of care due to its unique molecular properties: inhibition of the upregulated Hippo pathway that frequently drives soft tissue sarcoma and photodynamic therapy-mediated necrosis due to oxidative damage. The initial anti-proliferative effect of verteporfin is mediated via binding and dissociation of YAP/TEAD proteins from the nucleus, ultimately leading to decreased cell proliferation as demonstrated in multiple in vitro studies. This effect has the potential to be compounded with use of photodynamic therapy to directly induce cellular necrosis with use of a clinical laser. Photodynamic therapy has been incorporated into multiple malignancies and has the potential to be incorporated into sarcoma treatment.

Treatment of Catatonia With Ultrabrief Right Unilateral Electroconvulsive Therapy: A Case Series.

Catatonia is a syndrome heterogeneous with regard to presentation and etiology. Electroconvulsive therapy (ECT) remains the first-line treatment for catatonia. Literature review reveals only a few published case reports on the use of right unilateral (RUL) ECT in catatonia, 1 case report on ultrabrief RUL ECT, and an absence of evidence on the relative effectiveness and tolerability of RUL versus bilateral ECT in treating catatonia. In contrast, there are multiple reports in the literature of robustly dosed bilateral ECT, often administered on consecutive days. Reasons for choosing this intervention over the better-tolerated RUL treatment include assumptions about its relative speed and/or breadth of efficacy. Here we present a case series of 13 catatonic patients treated in an academic center over the course of the last 3 years. Our experience suggests that ultrabrief RUL ECT can rapidly and effectively treat catatonia from diverse etiologies.

Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial.

IMPORTANCE: This research examines the impact of 4 weeks of repetitive transcranial magnetic stimulation (rTMS) stimulation to the temporoparietal junction and compares the results of this longer duration of treatment with a similar stimulus protocol of only 2 weeks' duration. OBJECTIVE: To examine the effectiveness and safety of 4 weeks of low-frequency rTMS to the left temporoparietal junction in a cohort of patients with bothersome tinnitus. DESIGN: Crossover, double-blind, randomized controlled trial. SETTING: Outpatient academic medical center. PARTICIPANTS: The study population comprised 14 adults aged between 22 and 59 years with subjective, unilateral or bilateral, nonpulsatile tinnitus of 6 months' duration or greater and a score of 34 or greater on the Tinnitus Handicap Inventory (THI). INTERVENTIONS: Low-frequency (1 Hz) 110% motor threshold rTMS or sham to the left temporoparietal junction for 4 weeks. MAIN OUTCOME AND MEASURE: The difference of the change in the THI score between active rTMS and sham rTMS. RESULTS: Active treatment was associated with a median reduction in THI score of 10 (range, -20 to +4) points, and sham treatment was associated with a median reduction of 6 (range, -24 to +12) points. The median difference in THI score between the change associated with active and sham rTMS was 4 (95% CI, -9 to 10; and range, -32 to +14) points. CONCLUSIONS AND RELEVANCE: Daily low-frequency active rTMS to the left temporoparietal junction area for 4 weeks was no more effective than sham for patients with chronic bothersome tinnitus. Possible explanations for this negative study include the failure of rTMS to stimulate deeper parts of auditory cortex within the sylvian fissure and more widespread cortical network changes not amenable to localized rTMS effects. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00567892.

Cognitive improvement following treatment in late-life depression: relationship to vascular risk and age of onset.

OBJECTIVES: To test the hypothesis that the degree of vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late-life depression. DESIGN: Measurement of cognition both before and following 12 weeks of treatment with sertraline. SETTING: University medical centers (Washington University and Duke University). PARTICIPANTS: One hundred sixty-six individuals with late-life depression. INTERVENTION: Sertraline treatment. MEASUREMENTS: The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2-based white matter hyperintensities using the Fazekas criteria. RESULTS: Both episodic memory and executive function demonstrated significant improvement among adults with late-life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental State Examination scores predicted less change in working memory. Furthermore, older age, later age of onset, and higher vascular risk scores predicted less change in executive function. CONCLUSIONS: These results have important clinical implications in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.

Altered networks in bothersome tinnitus: a functional connectivity study.

BACKGROUND: The objective was to examine functional connectivity linked to the auditory system in patients with bothersome tinnitus. Activity was low frequency (< 0.1 Hz), spontaneous blood oxygenation level-dependent (BOLD) responses at rest. The question was whether the experience of chronic bothersome tinnitus induced changes in synaptic efficacy between co-activated components. Functional connectivity for seed regions in auditory, visual, attention, and control networks was computed across all 2 mm(3) brain volumes in 17 patients with moderate-severe bothersome tinnitus (Tinnitus Handicap Index: average 53.5 ± 3.6 (range 38-76)) and 17 age-matched controls. RESULTS: In bothersome tinnitus, negative correlations reciprocally characterized functional connectivity between auditory and occipital/visual cortex. Negative correlations indicate that when BOLD response magnitudes increased in auditory or visual cortex they decreased in the linked visual or auditory cortex, suggesting reciprocally phase reversed activity between functionally connected locations in tinnitus. Both groups showed similar connectivity with positive correlations within the auditory network. Connectivity for primary visual cortex in tinnitus included extensive negative correlations in the ventral attention temporoparietal junction and in the inferior frontal gyrus and rostral insula - executive control network components. Rostral insula and inferior frontal gyrus connectivity in tinnitus also showed greater negative correlations in occipital cortex. CONCLUSIONS: These results imply that in bothersome tinnitus there is dissociation between activity in auditory cortex and visual, attention and control networks. The reciprocal negative correlations in connectivity between these networks might be maladaptive or reflect adaptations to reduce phantom noise salience and conflict with attention to non-auditory tasks.

Effects of severe bothersome tinnitus on cognitive function measured with standardized tests.

Neurocognitive tests compared abilities in people with bothersome tinnitus against an age-, gender-, and education-matched normative population. Participants between 18 and 60 years had subjective, unilateral or bilateral, nonpulsatile tinnitus for >6 months and a Tinnitus Handicap Inventory score of ≥ 38. Results from a first testing session showed deficits in learning, learning rates, immediate recall of heard words, and use of a serial order encoding strategy. Initial reliance on serial order encoding and, later, increased intrusion of incorrect words towards normal levels might indicate a less demanding strategy to compensate for weakness in associative memory for semantic categories.

Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus.

OBJECTIVE: To examine the effectiveness and safety of low-frequency repetitive transcranial magnetic stimulation (rTMS) to the temporoparietal junction in a cohort of patients with bothersome tinnitus. DESIGN: Crossover, double-blind, randomized clinical trial. SETTING: Outpatient academic medical center. PARTICIPANTS: Fourteen adults aged 42 to 59 years with subjective, unilateral or bilateral, nonpulsatile tinnitus of 6 months' duration or longer and a score of 38 or greater on the Tinnitus Handicap Inventory (THI). INTERVENTIONS: Low-frequency (1-Hz) 110% motor threshold rTMS or sham treatment to the left temporoparietal junction for 2 weeks. MAIN OUTCOME MEASURE: The difference in the change of the THI score between active and sham rTMS. RESULTS: Active treatment was associated with a median (95% confidence interval) reduction in THI score of 5 (0-14) points, and sham treatment was associated with a median reduction in THI score of 6 (-2 to 12) points. The difference in THI scores between the change associated with active and sham rTMS ranged from a 34-point reduction in THI score after active treatment to a 22-point increase after sham treatment, with a median difference change of only 1 point (-6 to 4 points). CONCLUSIONS: Daily low-frequency rTMS to the left temporoparietal junction area for 2 weeks is no more effective than placebo for patients with chronic bothersome tinnitus. Possible explanations for the negative findings are short duration of treatment, failure of rTMS stimulation over the temporoparietal area to affect the auditory cortex buried within the Sylvian fissure, or more widespread cortical network changes associated with severe bothersome tinnitus not amenable to localized rTMS effects. Trial Registration clinicaltrials.gov Identifier: NCT00567892.

Repetitive transcranial magnetic stimulation treats postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a prevalent illness, affecting 10-15% of new mothers. PPD is the most common complication of childbirth and is a significant public health concern. It is known to adversely impact maternal-infant bonding, childrearing practices, and can lead to suicide and infanticide. The current treatment approaches to PPD are suboptimal. Many mothers are reluctant to take medication because of concerns about side effects or exposure of their newborn infant through breastfeeding. The specific aims of this study were to (1) examine acute treatment effectiveness, (2) examine response durability, and (3) assess an effect of repetitive transcranial magnetic stimulation (rTMS) on maternal bonding. METHODS: Nine antidepressant-free women with PPD were given 20 rTMS treatments over 4 weeks (10Hz, 120% motor threshold, left dorsolateral prefrontal cortex). Multiple characteristics were assessed at baseline and throughout treatment. Duration of effect was assessed at 30 days, 3 months and 6 months posttreatment. RESULTS: Friedman's tests were conducted on Hamilton Rating Scale for Depression-24 item (HRSD-24), Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology-Self-Report (IDS-SR) and Clinical Global Impressions-Severity (CGI-S) scores to compare performances at four time points (baseline, end of Week 2, end of Week 4, and 180-day follow-up). Overall, these results revealed a significant reduction in depressive symptoms by the end of Week 2 of treatment. Analyses yielded a medium effect size (r=0.68) on the primary outcome variable (HRSD-24). Of note, all nine patients remained in treatment for the complete 4 weeks, did not miss any treatment sessions and eight participants achieved remission of symptoms, defined as a HRSD<10 and a CGI-S=1. Analysis of follow-up data indicated robustness of the rTMS treatment over time. At 6-month follow-up, of the eight women that remitted, seven remained in remission without further psychiatric intervention, including the addition of medication and one was lost to follow-up. Results also indicated a significant improvement in bonding. CONCLUSIONS: Our results demonstrate promising results for the use of rTMS in the treatment of PPD. Further randomized, sham-controlled studies need to be completed.

Support for the vascular depression hypothesis in late-life depression: results of a 2-site, prospective, antidepressant treatment trial.

CONTEXT: Research on vascular depression has used 2 approaches to subtype late-life depression, based on executive dysfunction or white matter hyperintensity severity. OBJECTIVE: To evaluate the relationship of neuropsychological performance and white matter hyperintensity with clinical response in late-life depression. DESIGN: Two-site, prospective, nonrandomized controlled trial. SETTING: Outpatient clinics at Washington University and Duke University. PARTICIPANTS: A total of 217 subjects aged 60 years or older met DSM-IV criteria for major depression, scored 20 or more on the Montgomery-Asberg Depression Rating Scale (MADRS), and received vascular risk factor scores, neuropsychological testing, and magnetic resonance imaging; they were excluded for cognitive impairment or severe medical disorders. Fazekas rating was conducted to grade white matter hyperintensity lesions. Intervention Twelve weeks of sertraline treatment, titrated by clinical response. Main Outcome Measure Participants' MADRS scores over time. RESULTS: Baseline neuropsychological factor scores correlated negatively with baseline Fazekas scores. A mixed model examined effects of predictor variables on MADRS scores over time. Baseline episodic memory (P = .002), language (P = .007), working memory (P = .01), processing speed (P < .001), executive function factor scores (P = .002), and categorical Fazekas ratings (P = .05) predicted MADRS scores, controlling for age, education, age of onset, and race. Controlling for baseline MADRS scores, these factors remained significant predictors of decrease in MADRS scores, except for working memory and Fazekas ratings. Thirty-three percent of subjects achieved remission (MADRS < or =7). Remitters differed from nonremitters in baseline cognitive processing speed, executive function, language, episodic memory, and vascular risk factor scores. CONCLUSIONS: Comprehensive neuropsychological function and white matter hyperintensity severity predicted MADRS scores prospectively over a 12-week treatment course with selective serotonin reuptake inhibitors in late-life depression. Baseline neuropsychological function differentiated remitters from nonremitters and predicted time to remission in a proportional hazards model. Predictor variables correlated highly with vascular risk factor severity. These data support the vascular depression hypothesis and highlight the importance of linking subtypes based on neuropsychological function and white matter integrity. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00045773.

Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects.

CONTEXT: Medication resistance is the leading indication for use of electroconvulsive therapy (ECT) in major depression. The practice of stopping antidepressant medications prior to ECT derived from studies in the 1960s and 1970s in nonresistant samples. There is also continuing controversy regarding the relative efficacy and adverse effects of right unilateral and bilateral ECT. OBJECTIVE: To test the hypotheses that, compared with placebo, concomitant treatment with nortriptline or venlafaxine during the ECT course enhances short-term efficacy without a meaningful effect on adverse effects and reduces the rate of post-ECT relapse, and to test the hypotheses that high-dose, right-sided, unilateral ECT is equivalent in efficacy to moderate-dosage bilateral ECT and retains advantages with respect to cognitive adverse effects. DESIGN: Prospective, randomized, triple-masked, placebo-controlled study conducted from 2001 through 2005. SETTING: Three university-based hospitals. PATIENTS: Of approximately 750 consecutive patients referred for ECT, 319 with a major depressive episode consented, were randomized to pharmacological or ECT treatment conditions, and received at least 1 ECT treatment. MAIN OUTCOME MEASURES: Scores on the Hamilton Rating Scale for Depression, remission rate following completion of ECT, and selective measures of cognitive adverse effects. RESULTS: Treatment with nortriptyline enhanced the efficacy and reduced the cognitive adverse effects of ECT relative to placebo. Venlafaxine resulted in a weaker degree of improvement and tended to worsen cognitive adverse effects. High-dosage right unilateral ECT did not differ or was superior to bilateral ECT in efficacy and resulted in less severe amnesia. CONCLUSIONS: The efficacy of ECT is substantially increased by the addition of an antidepressant medication, but such medications may differ in whether they reduce or increase cognitive adverse effects. High-dose, right-sided, unilateral ECT is at least equivalent to moderate-dosage bilateral ECT in efficacy, but retains advantages with respect to cognitive adverse effects.

Brain stimulation & the treatment of refractory psychiatric disorders.

Many patients with psychiatric disorders are refractory to current treatments, prompting a search for novel therapies. Based on the efficacy of electroconvulsive therapy, there is interest in developing other brain stimulation methods in psychiatry. Alternatives include vagal nerve stimulation, repetitive transcranial magnetic stimulation and deep brain stimulation. This paper reviews these methods, highlighting strategies currently being used and developed at Washington University and Barnes-Jewish Hospital in St. Louis.

Antidepressant efficacy of olanzapine as monotherapy in major depressive disorder, without psychosis: a pilot study.

In this pilot study we assessed the efficacy of olanzapine as monotherapy in the treatment of major depressive disorder, without psychosis. We also demonstrated the in vivo 5-HT2A receptor occupancy of olanzapine using positron emission tomography. An open-label prospective 6-week study design with 14 patients who met the inclusion and exclusion criteria for the study were enrolled from the general community of the St. Louis metropolitan area. All patients met DSM-IV criteria for major depressive disorder without psychosis, had a Hamilton Depression Rating Scale (HAMD17) score >18 and were between the ages of 18 and 65. The primary measure of efficacy was the change in HAMD 17 total score from baseline to endpoint. The data were collected between 1998 and 2004. There was a significant reduction in the HAMD17 scores from baseline to endpoint. Half the patients (n=6) showed > or =50% reduction in their HAMD17 scores. This study points to the potential of olanzapine as a therapeutic agent for the treatment of major depressive disorder without psychosis.

Cognitive function in late life depression: relationships to depression severity, cerebrovascular risk factors and processing speed.

BACKGROUND: A number of studies have examined clinical factors linked to worse neuropsychological performance in late life depression (LLD). To understand the influence of LLD on cognition, it is important to determine if deficits in a number of cognitive domains are relatively independent, or mediated by depression- related deficits in a basic domain such as processing speed. METHODS: Patients who met DSM-IV criteria for major depression (n = 155) were administered a comprehensive neuropsychological battery of tasks grouped into episodic memory, language, working memory, executive function, and processing speed domains. Multiple regression analyses were conducted to determine contributions of predictor variables to cognitive domains. RESULTS: Age, depression severity, education, race and vascular risk factors all made significant and independent contributions to one or more domains of cognitive function, with all five making independent contributions to processing speed. Age of onset made no independent contribution, after accounting for age and vascular risk factors. Of the five cognitive domains investigated, changes in processing speed were found to most fully mediate the influence of predictor variables on all other cognitive domains. CONCLUSIONS: While slowed processing speed appears to be the most core cognitive deficit in LLD, it was closely followed by executive function as a core cognitive deficit. Future research is needed to help clarify mechanisms leading to LLD- related changes in processing speed, including the potential role of white matter abnormalities.

Low frequency rTMS stimulation of the right frontal cortex is as effective as high frequency rTMS stimulation of the left frontal cortex for antidepressant-free, treatment-resistant depressed patients.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising relatively non-invasive alternative for the treatment of depression. The purpose of this study was to compare the apparent effectiveness of high frequency (20 Hertz) rTMS applied over the left dorsolateral prefrontal cortex (DLPFC) with that of low frequency (1 Hz) rTMS applied over the right DLPFC METHODS: Twenty-eight antidepressant-free adults with major depressive (n = 25) or bipolar (n = 3) disorder (not on mood stabilizers) in a current major depression (Hamilton Rating Scale for Depression [HAM-D-21] > or = 18; Mean = 24.5, SD = 5.51) were treated (14 right, 14 left) for 4 weeks. RESULTS: Overall paired t-tests revealed a significant reduction in mean HAM-D-21, Beck Depression Inventory (BDI-II), and Clinical Global Impression of Change (CGIC) scores at the end of treatment for both groups (high frequency left DLPFC and low frequency right DLPFC). The treatment response rate found (32%) was typical of other response rates reported in the literature (6,30). One-month follow-up data was obtained from 50% of participants. At 1-month follow-up no significant differences were noted as compared to patients' performance at last treatment visit, indicating moderate robustness of rTMS treatment over time. Furthermore, magnetic stimulation did not substantially alter patient memory over the course of treatment. CONCLUSION: rTMS given at low frequency over the right frontal cortex appears to be as effective treatment of refractory depression as high frequency treatment over the left frontal cortex.

Covariation of alternative measures of responding in rabbit (Oryctolagus cuniculus) eyeblink conditioning during acquisition training and tone generalization.

The likelihood, size, and speed of eyelid movements are thought to covary during the acquisition and expression of conditioning in rabbits (Oryctolagus cuniculus) and are generally accepted as interchangeable measures of the associative strength activated by the conditioned stimulus (CS). To test this assumption, the authors examined the patterns of covariation in these eyelid movement measures in acquisition and stimulus generalization in the upper eyelid and nictitating membrane. Rather than the expected covariation among these measures, eyelid movement magnitudes during the CS were distributed in approximately a bimodal manner. That is, eyelid activity consisted largely of a mixture of very small (< 0.125 mm) baseline measurements and larger (> 1 mm) movements. The results are discussed with respect to their implications for real-time models of eyelid conditioning.