Body temperature of bitches in the first week after parturition measured by ingestible loggers.

The objective of this study was to identify the physiological ranges of body temperature of bitches in the first 7 days after parturition by measurement with ingestible temperature loggers. Twenty bitches swallowed one ingestible temperature logger daily. Bitches were defined to be healthy by spontaneous parturition and leucocyte concentration. Mean core body temperatures of eight healthy bitches were (Mean ± SD) 38.8°C ± 0.40 on day 0 p.p., 38.9°C ± 0.47 on day 1 p.p., 38.9°C ± 0.35 on day 2 p.p. 38.7°C ± 0.31 on day 3 p.p., respectively. In the following days, the three remaining healthy bitches showed mean core body temperatures (Mean ± SD) of 38.8°C ± 0.30 on day 4 p.p., 38.6°C ± 0.35 on day 5 p.p., 38.5°C ± 0.27 on day 6 p.p. and 38.4°C ± 0.34 on day 7 p.p., respectively. Three out of the eight healthy bitches showed temperatures ≥39.5°C. Bitches with leucocytosis showed significant higher mean core body temperatures (39.0°C ± 0.49) than healthy bitches (38.8°C ± 0.39) during the first 3 days after parturition (p < 0.01). We conclude that the physiological ranges of body temperature of healthy bitches in the first days after parturition do not differ from those of healthy dogs in general, while the appearance of short episodes of febrile temperatures seems to be physiological. Puerperal bitches with leucocytosis show higher body temperatures increased by only 0.2°C.

The Efficacy of "Foundations," a Digital Mental Health App to Improve Mental Well-being During COVID-19: Proof-of-Principle Randomized Controlled Trial.

BACKGROUND: Against a long-term trend of increasing demand, the COVID-19 pandemic has led to a global rise in common mental disorders. Now more than ever, there is an urgent need for scalable, evidence-based interventions to support mental well-being. OBJECTIVE: The aim of this proof-of-principle study was to evaluate the efficacy of a mobile-based app in adults with self-reported symptoms of anxiety and stress in a randomized control trial that took place during the first wave of the COVID-19 pandemic in the United Kingdom. METHODS: Adults with mild to severe anxiety and moderate to high levels of perceived stress were randomized to either the intervention or control arm. Participants in the intervention arm were given access to the Foundations app for the duration of the 4-week study. All participants were required to self-report a range of validated measures of mental well-being (10-item Connor-Davidson Resilience scale [CD-RISC-10], 7-item Generalized Anxiety Disorder scale [GAD-7], Office of National Statistics Four Subjective Well-being Questions [ONS-4], World Health Organization-5 Well-Being Index [WHO-5]) and sleep (Minimal Insomnia Scale [MISS]) at baseline and at weeks 2 and 4. The self-reported measures of perceived stress (10-item Perceived Stress Score [PSS-10]) were obtained weekly. RESULTS: A total of 136 participants completed the study and were included in the final analysis. The intervention group (n=62) showed significant improvements compared to the control group (n=74) on measures of anxiety, with a mean GAD-7 score change from baseline of -1.35 (SD 4.43) and -0.23 (SD 3.24), respectively (t134=1.71, P=.04); resilience, with a mean change in CD-RISC score of 1.79 (SD 4.08) and -0.31 (SD 3.16), respectively (t134=-3.37, P<.001); sleep, with a mean MISS score change of -1.16 (SD 2.67) and -0.26 (SD 2.29), respectively (t134=2.13, P=.01); and mental well-being, with a mean WHO-5 score change of 1.53 (SD 5.30) and -0.23 (SD 4.20), respectively (t134=-2.16, P=.02), within 2 weeks of using Foundations, with further improvements emerging at week 4. Perceived stress was also reduced within the intervention group, although the difference did not reach statistical significance relative to the control group, with a PSS score change from baseline to week 2 of -2.94 (SD 6.84) and -2.05 (SD 5.34), respectively (t134= 0.84, P=.20). CONCLUSIONS: This study provides a proof of principle that the digital mental health app Foundations can improve measures of mental well-being, anxiety, resilience, and sleep within 2 weeks of use, with greater effects after 4 weeks. Foundations therefore offers potential as a scalable, cost-effective, and accessible solution to enhance mental well-being, even during times of crisis such as the COVID-19 pandemic. TRIAL REGISTRATION: OSF Registries osf.io/f6djb; https://osf.io/vm3xq.

Dorsomedial prefrontal cortex repetitive transcranial magnetic stimulation for treatment-refractory major depressive disorder: A three-arm, blinded, randomized controlled trial.

BACKGROUND: Dorsomedial prefrontal cortex (DMPFC) repetitive transcranial magnetic stimulation (rTMS) is a novel intervention for treatment-refractory depression (TRD). To date, many open-label case series and one randomized controlled trial of modest sample size have provided preliminary evidence that DMPFC-rTMS is an effective treatment for TRD. Here, we report the results of a large, double-blinded, sham-controlled trial of DMPFC-rTMS for TRD. OBJECTIVE: The primary aim of this study was to determine the efficacy of DMPFC-rTMS for TRD under sham-controlled conditions. METHODS: 120 TRD patients were randomized to receive 30 twice-daily sessions of either active high-frequency, active low-frequency, or sham DMPFC-rTMS using a novel bent active/sham double-cone coil. Placebo stimulation also involved the use of surface electrodes placed above the eyebrows. The 17-item Hamilton Rating Scale for Depression served as the primary outcome measure. RESULTS: Although there was a significant main effect of treatment across all arms, active DMPFC-rTMS was not superior to sham. Both participants and assessors were unable to accuracy determine whether patients received active or placebo stimulation. However, technicians' treatment arm guesses were significantly above chance. CONCLUSION: DMPFC rTMS did not result in improvement of depressive symptoms greater than sham stimulation. We cannot rule out that the sham apparatus may also have elicited an antidepressant effect via electrical trigeminal stimulation; future DMPFC-rTMS trials are therefore warranted.

Clinical, behavioral, and neural measures of reward processing correlate with escitalopram response in depression: a Canadian Biomarker Integration Network in Depression (CAN-BIND-1) Report.

Anhedonia is thought to reflect deficits in reward processing that are associated with abnormal activity in mesocorticolimbic brain regions. It is expressed clinically as a deficit in the interest or pleasure in daily activities. More severe anhedonia in major depressive disorder (MDD) is a negative predictor of antidepressant response. It is unknown, however, whether the pathophysiology of anhedonia represents a viable avenue for identifying biological markers of antidepressant treatment response. Therefore, this study aimed to examine the relationships between reward processing and response to antidepressant treatment using clinical, behavioral, and functional neuroimaging measures. Eighty-seven participants in the first Canadian Biomarker Integration Network in Depression (CAN-BIND-1) protocol received 8 weeks of open-label escitalopram. Clinical correlates of reward processing were assessed at baseline using validated scales to measure anhedonia, and a monetary incentive delay (MID) task during functional neuroimaging was completed at baseline and after 2 weeks of treatment. Response to escitalopram was associated with significantly lower self-reported deficits in reward processing at baseline. Activity during the reward anticipation, but not the reward consumption, phase of the MID task was correlated with clinical response to escitalopram at week 8. Early (baseline to week 2) increases in frontostriatal connectivity during reward anticipation significantly correlated with reduction in depressive symptoms after 8 weeks of treatment. Escitalopram response is associated with clinical and neuroimaging correlates of reward processing. These results represent an important contribution towards identifying and integrating biological, behavioral, and clinical correlates of treatment response. ClinicalTrials.gov: NCT01655706.

A Real-Time Phase-Locking System for Non-invasive Brain Stimulation.

Non-invasive brain stimulation techniques are entering widespread use for the investigation and treatment of a range of neurological and neuropsychiatric disorders. However, most current techniques are 'open-loop', without feedback from target brain region activity; this limitation could contribute to heterogeneous effects seen for nominally 'inhibitory' and 'excitatory' protocols across individuals. More potent and consistent effects may ensue from closed-loop and, in particular, phase-locked brain stimulation. In this work, a closed-loop brain stimulation system is introduced that can analyze EEG data in real-time, provide a forecast of the phase of an underlying brain rhythm of interest, and control pulsed transcranial electromagnetic stimulation to deliver pulses at a specific phase of the target frequency band. The technique was implemented using readily available equipment such as a basic EEG system, a low-cost Arduino board and MATLAB scripts. The phase-locked brain stimulation method was tested in 5 healthy volunteers and its phase-locking performance evaluated at 0, 90, 180, and 270 degree phases in theta and alpha frequency bands. On average phase locking values of 0.55° ± 0.11° and 0.52° ± 0.14° and error angles of 11° ± 11° and 3.3° ± 18° were achieved for theta and alpha stimulation, respectively. Despite the low-cost hardware implementation, signal processing time generated a phase delay of only 3.8° for theta and 57° for alpha stimulation, both readily accommodated in the pulse trigger algorithm. This work lays the methodological steps for achieving phase-locked brain stimulation for brief-pulse transcranial electrical stimulation (tES) and repetitive transcranial magnetic stimulation (rTMS), facilitating further research on the effect of stimulation phase for these techniques.

Number of pulses or number of sessions? An open-label study of trajectories of improvement for once-vs. twice-daily dorsomedial prefrontal rTMS in major depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) shows efficacy in the treatment of major depressive episodes (MDEs), but can require ≥4-6 weeks for maximal effect. Recent studies suggest that multiple daily sessions of rTMS can accelerate response without reducing therapeutic efficacy. However, it is unresolved whether therapeutic effects track cumulative number of pulses, or cumulative number of sessions. OBJECTIVE: This open-label study reviewed clinical outcomes over a 20-30 session course of high-frequency bilateral dorsomedial prefrontal cortex (DMPFC)-rTMS among patients receiving 6000 pulses/day delivered either in twice-daily sessions 80 min apart (at 20 Hz) or single, longer, once-daily sessions (at 10 Hz). METHODS: A retrospective chart review identified 130 MDD patients who underwent 20-30 daily sessions of bilateral DMPFC-rTMS (Once-daily, n = 65; Twice-daily, n = 65) at a single Canadian clinic. RESULTS: Mixed-effects modeling revealed significantly faster improvement (group-by-time interaction) for twice-daily versus once-daily DMPFC-rTMS. Across both groups, the pace of improvement showed a consistent relationship with number of cumulative sessions, but not with cumulative number of pulses. Although the twice-daily group completed treatment in half as many days, final clinical outcomes did not differ significantly between groups on dichotomous measures (response/remission rates: once-daily, 35.4%/33.8%; twice-daily, 41.5%/35.4%), or continuous measures, or on overall response distribution. CONCLUSIONS: Twice-daily rTMS appears feasible, tolerable, and capable of achieving comparable results to once-daily rTMS, while also reducing course length approximately twofold. Therapeutic gains tracked the cumulative number of sessions, not pulses. Future randomized studies comparing once-daily to multiple-daily rTMS sessions, while controlling for number of pulses, may be warranted.

Cortico-Striatal-Thalamic Loop Circuits of the Orbitofrontal Cortex: Promising Therapeutic Targets in Psychiatric Illness.

Corticostriatal circuits through the orbitofrontal cortex (OFC) play key roles in complex human behaviors such as evaluation, affect regulation and reward-based decision-making. Importantly, the medial and lateral OFC (mOFC and lOFC) circuits have functionally and anatomically distinct connectivity profiles which differentially contribute to the various aspects of goal-directed behavior. OFC corticostriatal circuits have been consistently implicated across a wide range of psychiatric disorders, including major depressive disorder (MDD), obsessive compulsive disorder (OCD), and substance use disorders (SUDs). Furthermore, psychiatric disorders related to OFC corticostriatal dysfunction can be addressed via conventional and novel neurostimulatory techniques, including deep brain stimulation (DBS), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS). Such techniques elicit changes in OFC corticostriatal activity, resulting in changes in clinical symptomatology. Here we review the available literature regarding how disturbances in mOFC and lOFC corticostriatal functioning may lead to psychiatric symptomatology in the aforementioned disorders, and how psychiatric treatments may exert their therapeutic effect by rectifying abnormal OFC corticostriatal activity. First, we review the role of OFC corticostriatal circuits in reward-guided learning, decision-making, affect regulation and reappraisal. Second, we discuss the role of OFC corticostriatal circuit dysfunction across a wide range of psychiatric disorders. Third, we review available evidence that the therapeutic mechanisms of various neuromodulation techniques may directly involve rectifying abnormal activity in mOFC and lOFC corticostriatal circuits. Finally, we examine the potential of future applications of therapeutic brain stimulation targeted at OFC circuitry; specifically, the role of OFC brain stimulation in the growing field of individually-tailored therapies and personalized medicine in psychiatry.

Effect of antipsychotic pharmacotherapy on clinical outcomes of intermittent theta-burst stimulation for refractory depression.

Theta-burst stimulation is an emerging protocol for repetitive transcranial magnetic stimulation that takes 1-3 min to administer, yet offers equal/superior potency to conventional protocols lasting 30-60 min. However, preclinical evidence suggests that D2 receptor blockade may abolish the acute effects of theta-burst stimulation on synaptic facilitation or inhibition. As many patients presenting for repetitive transcranial magnetic stimulation are taking antipsychotic medications as augmentation for treatment-resistant depression, this finding is potentially concerning for the implementation of theta-burst stimulation in clinical settings. Here, we examined whether treatment-resistant depression patients taking antipsychotics have worse outcomes after a course of intermittent theta-burst stimulation. A chart review identified 105 treatment-resistant depression patients who underwent dorsomedial prefrontal-intermittent theta-burst stimulation; clinical outcomes on Hamilton Depression Rating Scale and Beck Depression Inventory were compared for those taking and not taking antipsychotics. The 29 of 105 patients who were taking antipsychotics showed non-significantly better response and remission rates, and non-significantly larger percentage improvements on both scales, with a positive but non-significant correlation between higher antipsychotic dose and larger percentage improvement. Contrary to expectations, outcomes were not significantly worse, and in some analyses trended towards being better, in patients taking antipsychotics. Future randomized controlled studies of repetitive transcranial magnetic stimulation combined with standardized dopaminergic manipulations may be justified and warranted.

Cognitive safety of dorsomedial prefrontal repetitive transcranial magnetic stimulation in major depression.

The most widely used target for repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD) is the dorsolateral prefrontal cortex (DLPFC). Despite convergent evidence that the dorsomedial prefrontal cortex (DMPFC) may be a promising alternative target for rTMS in TRD, its cognitive safety profile has not previously been assessed. Here, we applied 20 sessions of rTMS to the DMPFC in 21 TRD patients. Before and after treatment, a battery of neuropsychological tasks was administered to evaluate changes in cognition across three general cognitive domains: learning and memory, attention and processing speed, and cognitive flexibility. Subjects also completed the 17-item Hamilton Rating Scale for Depression (HamD17) prior to and following treatment to measure changes in severity of depressive symptoms, and to assess the relationship between mood and cognitive performance over the course of treatment. No serious adverse effects or significant deterioration in cognitive performance were observed. Overall, subjects improved significantly on Stroop Inhibition/Switching and on Trails B, and this improvement was independent of the degree of improvement in depression symptoms. No domains or items significantly predicted clinical outcome, with the exception of baseline performance on Visual Elevator Accuracy. Clinical improvement correlated to improved performance in the overall domain of attention and processing speed, although this effect was not evident following covariate adjustment. DMPFC-rTMS did not produce any detectable cognitive adverse effects during treatment of TRD. Performance did not deteriorate significantly on any measures. Taken together, the present findings support the tolerability and cognitive safety of DMPFC-rTMS in refractory depression.

Gender and the council of emergency medicine residency directors standardized letter of recommendation.

OBJECTIVES: Until 2002, the Council of Emergency Medicine Residency Directors standardized letter of recommendation (SLOR) prompted authors to predict how an applicant would rank on their match list. A ranking of guaranteed match (GM) was identified as the least common superlative response on the SLOR. That knowledge allowed precise identification of the best SLORs. The authors correlated GM with every possible author/applicant gender combination. METHODS: This was a retrospective, observational study of 835 SLORs submitted in the 1998-1999 and 1999-2000 application cycles to one emergency medicine residency program. A standardized data collection instrument was used. Author/applicant gender combinations (M/M, M/F, F/F, F/M, M/M + F/F, and M/F + F/M) were analyzed with respect to GM by chi-square test, odds ratios with 95% confidence intervals, and logistic regression. RESULTS: There was a statistically significant association between a female-authored/female-applicant SLOR and GM, with a female applicant two times more likely to get a GM from a female author than any other author/applicant gender combination (odds ratio, 2.0; 95% confidence interval = 1.1 to 3.8; p = 0.023). No other combination was significantly associated with GM. CONCLUSIONS: Female applicants to the authors' emergency residency program had a two times better chance of receiving a GM recommendation on a SLOR written by a female faculty member compared with any other possible gender combination of applicants and letter authors. Although the choice of GM has now been eliminated from the SLOR, the role of gender in relation to the SLOR merits further study.

Antipsychotic response in first-episode schizophrenia: efficacy of high doses and switching.

Clinicians treating schizophrenia routinely employ high doses and/or antipsychotic switching to achieve response. However, little is actually known regarding the value of these interventions in early schizophrenia. Data were gathered from a treatment algorithm implemented in patients with first-episode schizophrenia that employs two antipsychotic trials at increasing doses before clozapine. Patients were initially treated with either olanzapine or risperidone across three dose ranges, (low, full, high), and in the case of suboptimal response were switched to the alternate antipsychotic. We were interested in the value of (a) high dose treatment and (b) antipsychotic switching. A total of 244 patients were evaluated, with 74.5% (184/244) responsive to Trial 1, and only 16.7% (10/60) responsive to Trial 2. Percentage of response for subjects switched from olanzapine to risperidone was 4.0% (1/25) vs. 25.7% (9/35) for those switched from risperidone to olanzapine. High doses yielded a 15.5% response (14.6% for risperidone vs. 16.7% for olanzapine).The present findings concur with other research indicating that response rate to the initial antipsychotic trial in first-episode schizophrenia is robust; thereafter it declines notably. In general, the proportion of responders to antipsychotic switching and high dose interventions was low. For both strategies olanzapine proved superior to risperidone, particularly in the case of antipsychotic switching (i.e. risperidone to olanzapine vs. vice versa). It remains to be established whether further antipsychotic trials are associated with even greater decrements in rate of response. Findings underscore the importance of moving to clozapine when treatment resistance has been established.