Cingulate dynamics track depression recovery with deep brain stimulation.

Deep brain stimulation (DBS) of the subcallosal cingulate (SCC) can provide long-term symptom relief for treatment-resistant depression (TRD)1. However, achieving stable recovery is unpredictable2, typically requiring trial-and-error stimulation adjustments due to individual recovery trajectories and subjective symptom reporting3. We currently lack objective brain-based biomarkers to guide clinical decisions by distinguishing natural transient mood fluctuations from situations requiring intervention. To address this gap, we used a new device enabling electrophysiology recording to deliver SCC DBS to ten TRD participants (ClinicalTrials.gov identifier NCT01984710). At the study endpoint of 24 weeks, 90% of participants demonstrated robust clinical response, and 70% achieved remission. Using SCC local field potentials available from six participants, we deployed an explainable artificial intelligence approach to identify SCC local field potential changes indicating the patient's current clinical state. This biomarker is distinct from transient stimulation effects, sensitive to therapeutic adjustments and accurate at capturing individual recovery states. Variable recovery trajectories are predicted by the degree of preoperative damage to the structural integrity and functional connectivity within the targeted white matter treatment network, and are matched by objective facial expression changes detected using data-driven video analysis. Our results demonstrate the utility of objective biomarkers in the management of personalized SCC DBS and provide new insight into the relationship between multifaceted (functional, anatomical and behavioural) features of TRD pathology, motivating further research into causes of variability in depression treatment.

Protein kinase D2 regulates epithelial sodium channel activity and aldosterone non-genomic responses in renal cortical collecting duct cells.

Protein kinase D2 (PKD2) is a serine/threonine protein kinase which plays an important role in vesicle fission at the trans-Golgi network (TGN) to coordinate subcellular trafficking with gene expression. We found that in the rat kidney, PKD2 is specifically expressed in collecting duct principal cells predominantly at the apical membrane and with lower basal expression in cytosolic compartments. When rats were maintained on a Na+ depleted diet (<0.87 mmol Na+/kg) to increase plasma aldosterone levels, PKD2 became internalized to a cytoplasmic compartment. Treatment of murine M1 cortical collecting duct (M1-CCD) cells with aldosterone (10 nM) promoted PKD2 co-localization with the trans-Golgi network within 30 min. PKD2 underwent autophosphorylation at Ser876 within 10 min of aldosterone treatment and remained phosphorylated (active) for at least 24 h. A stable PKD2 shRNA knock-down (PKD2 KD) M1-CCD cell line was developed to study the role of PKD2 in epithelial Na+ channel (ENaC) trafficking and transepithelial Na+ transport (SCC) in epithelial monolayers grown in Ussing chambers. The PKD2 KD cells developed transepithelial resistance with kinetics equivalent to wild-type cells, however the transepithelial voltage and Na+ current were significantly elevated in PKD2 knock-down CCD epithelia. The higher basal SCC was due to increased ENaC activity. Aldosterone treatment for 24 h resulted in a decline in ENaC activity in the PKD2 KD cells as opposed to the increase observed in the wild-type cells. The paradoxical inhibition of SCC by aldosterone in PKD2 KD epithelium was attributed to a reduction in ENaC current and lower membrane abundance of ENaC, demonstrating that PKD2 plays a critical tonic role in ENaC trafficking and channel subunit stability. The rapid activation of PKD2 by aldosterone is synergistic with the transcriptional activity of MR and contributes to increased ENaC activity.

Long-Term Outcomes of Subcallosal Cingulate Deep Brain Stimulation for Treatment-Resistant Depression.

OBJECTIVE: Deep brain stimulation of the subcallosal cingulate (SCC DBS) has been studied as a potential treatment for severe and refractory major depressive disorder since 2005. The authors used an open-label, long-term follow-up design to examine participants enrolled in a clinical trial of SCC DBS for treatment-resistant depression. METHODS: Long-term outcome data were collected for 28 patients (20 with major depressive disorder and seven with bipolar II disorder; one patient in the major depression subgroup was later reclassified as having bipolar II disorder) receiving SCC DBS for 4-8 years. RESULTS: Response and remission rates were maintained at ≥50% and ≥30%, respectively, through years 2-8 of the follow-up period. Three-quarters of all participants met the treatment-response criterion for more than half of their duration of participation in the study, with 21% of all patients demonstrating continuous response to treatment from the first year onward. Of 28 participants, 14 completed ≥8 years of follow-up, 11 completed ≥4 years, and three dropped out before 8 years. The procedure itself was generally safe and well tolerated, and there were no side effects of acute or chronic stimulation. The rate of medical or surgical complications was consistent with the rate observed in studies of DBS for other indications. There were no suicides. CONCLUSIONS: In >8 years of observation, most participants experienced a robust and sustained antidepressant response to SCC DBS.

When Medical News Comes from Press Releases-A Case Study of Pancreatic Cancer and Processed Meat.

The media have a key role in communicating advances in medicine to the general public, yet the accuracy of medical journalism is an under-researched area. This project adapted an established monitoring instrument to analyse all identified news reports (n = 312) on a single medical research paper: a meta-analysis published in the British Journal of Cancer which showed a modest link between processed meat consumption and pancreatic cancer. Our most significant finding was that three sources (the journal press release, a story on the BBC News website and a story appearing on the 'NHS Choices' website) appeared to account for the content of over 85% of the news stories which covered the meta analysis, with many of them being verbatim or moderately edited copies and most not citing their source. The quality of these 3 primary sources varied from excellent (NHS Choices, 10 of 11 criteria addressed) to weak (journal press release, 5 of 11 criteria addressed), and this variance was reflected in the accuracy of stories derived from them. Some of the methods used in the original meta-analysis, and a proposed mechanistic explanation for the findings, were challenged in a subsequent commentary also published in the British Journal of Cancer, but this discourse was poorly reflected in the media coverage of the story.

Rapid aldosterone actions on epithelial sodium channel trafficking and cell proliferation.

Aldosterone regulates blood pressure through its effects on the kidney and the cardiovascular system. Dysregulation of aldosterone signalling can result in hypertension which in turn can lead to chronic pathologies of the kidney such as renal fibrosis and nephropathy. Aldosterone acts by binding to the mineralocorticoid receptor (MR), which acts as a ligand-dependent transcription factor in target tissues such as segments of the distal nephron including the connecting tubule and cortical collecting duct (CCD). Aldosterone also promotes the activation of protein kinase signalling cascades that are coupled to growth factor receptors and act directly on specific substrates in the cell membrane or cytoplasm. The rapid actions of aldosterone can also modulate gene expression through the phosphorylation of transcription factors. Aldosterone is a key regulator of Na(+) conservation in the distal nephron, largely through multiple mechanisms that modulate the activity of the epithelial Na(+) channel (ENaC). Aldosterone transcriptionally up-regulates the ENaCα subunit and also up regulates serum and glucocorticoid-regulated kinase-1 (SGK1) that indirectly regulates the ubiquitination of ENaC subunits. Aldosterone promotes the activation of protein kinase D1 (PKD1) which can modify the activity of ENaC and other transporters through effects on sub-cellular trafficking. In M1-CCD cells, early sub-cellular trafficking causes the redistribution of ENaC subunits within minutes of treatment with aldosterone. ENaC subunits can also interact directly with phosphatidylinositide signalling intermediates in the membrane and the mechanism by which PKD isoforms regulate protein trafficking is through the control of vesicle fission from the trans Golgi network by activation of phosphatidylinositol 4-kinaseIIIß (PI4KIIIß).

Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has shown safety and efficacy for treatment-resistant depression, but requires daily treatment for 4-6 weeks. Accelerated TMS, with all treatments delivered over a few days, would have significant advantages in terms of access and patient acceptance. METHODS: Open-label accelerated TMS (aTMS), consisting of 15 rTMS sessions administered over 2 days, was tested in 14 depressed patients not responding to at least one antidepressant medication. Effects on depression, anxiety, and cognition were assessed the day following treatment, then after 3 and 6 weeks. RESULTS: No seizure activity was observed and only one patient had a serious adverse event (increased suicidal ideation). Two patients failed to complete a full course of aTMS treatments, and 36% did not complete all study visits. Depression and anxiety significantly decreased following aTMS treatments and improvements persisted 3 and 6 weeks later. Response rates immediately following treatment and at 3 and 6 weeks were 43, 36, and 36%, respectively. Remission rates at the same timepoints were 29, 36, and 29%. CONCLUSIONS: Accelerated TMS demonstrated an excellent safety profile with efficacy comparable to that achieved in daily rTMS in other trials. Limitations primarily include open-label treatment and a small sample size.

Bupropion decreases resting motor threshold: a case report.

BACKGROUND: Bupropion is associated with a dose-related increased seizure risk. This effect could correlate with a change in motor cortex excitability. Transcranial magnetic stimulation (TMS) can assess changes in motor cortical excitability by measuring resting motor threshold (RMT). METHODS: RMT was determined before and during 2 weeks concomitant administration of bupropion at two different doses (150 mg/d and 300 mg/d) in a 41-year-old woman enrolled in a study of repetitive TMS (rTMS) for the treatment of depression. RESULTS: RMT was significantly lower when the patient took 300 mg/d of bupropion compared with no bupropion and 150 mg/d of bupropion. When bupropion was reduced to 150 mg, RMT returned to the premedication level. CONCLUSIONS: Bupropion 300 mg/d increased cortical excitability as demonstrated by decreased RMT. This finding emphasizes the importance of assessing RMT regularly during rTMS treatment, especially in the context of new or changed doses of medications.

Engagement with dietary fibre and receptiveness to resistant starch in Australia.

OBJECTIVE: To investigate community engagement with the health benefits of dietary fibre (DF) and its potential as a framework for the promotion of increased consumption of resistant starch (RS). SETTING: A nationwide postal Food and Health Survey conducted in Australia by CSIRO Human Nutrition. SUBJECTS: Adults aged 18 years and above, selected at random from the Australian Electoral Roll (n 849). DESIGN: A cross-sectional design was employed to analyse ratings of (i) the importance of various RS health and functional claims and (ii) receptiveness to different foods as RS delivery vehicles, according to the respondents' level of fibre engagement as classified under the Precaution Adoption Process Model (PAPM) of Health Behaviour. RESULTS: There was a high level of recognition (89·5 %) of DF as being important for health. Significant gender differences were found for ratings of RS attributes and RS delivery options. Women were both more fibre-engaged than men and more receptive than men to RS and its potential benefits. Ratings of the acceptability of several foods as means of delivering RS revealed a general preference for healthy staples over indulgences, with the margin between acceptability of staples and indulgences increasing markedly with increased fibre engagement. CONCLUSIONS: Application of the PAPM to awareness of DF reveals a ready-made target group for health messages about RS and pockets of differential potential receptiveness. The findings support the promotion of RS as providing health benefits of DF with the added reduction of risk of serious disease, its delivery through healthy staples and the targeting of messages at both fibre-engaged individuals and women in general.

A double blind, placebo-controlled pilot study of galantamine augmentation of antidepressant treatment in older adults with major depression.

OBJECTIVE: Depression in older adults is often associated with cognitive abnormalities and may predict later development of a primary cognitive disorder. This double-blind, randomized, placebo-controlled pilot study was designed to assess the safety and efficacy of galantamine augmentation of antidepressant treatment for depressive and cognitive symptoms in older adults with major depression. METHODS: Thirty-eight, non-demented older adults (age >50) with major depression were randomized to receive galantamine or placebo augmentation of standard antidepressant pharmacotherapy (venlafaxine XR or citalopram). Mood and cognitive status were monitored for 24 weeks using the 24-item Hamilton Rating Scale for Depression and the Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: Both groups showed significant improvements in mood and cognition over 24 weeks, but no significant difference was found in change over time between groups. An exploratory post-hoc analysis suggested that patients randomized to galantamine had lower depression scores compared to patients in the placebo group after 2 weeks of treatment. Dropout was high with more subjects randomized to antidepressant plus galantamine withdrawing early from the study. CONCLUSIONS: This pilot study failed to demonstrate a benefit for galantamine augmentation of antidepressant medication in the treatment of depression in older adults. Future studies should explore strategies for reducing dropout in such longitudinal trials and more carefully assess time to response with cholinesterase inhibitor augmentation.

Morphologic alterations in the corpus callosum in abuse-related posttraumatic stress disorder: a preliminary study.

Magnetic resonance imaging (MRI) studies in children with maltreatment-related posttraumatic stress disorder (PTSD) have demonstrated smaller corpus callosum area, with the greatest magnitude of change in posterior portions of the corpus callosum. The purpose of this study was to measure corpus callosum area in adult female patients with childhood abuse-related PTSD and comparison subjects. MRI was used to measure the midsagittal area of the corpus callosum as well as subregions of the corpus callosum in 9 female subjects with abuse-related PTSD and 9 healthy female subjects. No differences were found in total area of the corpus callosum or in individual subregions, but the subregion/total area ratio was significantly smaller in posterior midbody in PTSD compared with the healthy subjects. These results suggest that relatively smaller areas of the posterior midbody of the corpus callosum are associated with childhood abuse related PTSD in adults; these findings are consistent with findings in children with abuse-related PTSD.

Smaller volume of anterior cingulate cortex in abuse-related posttraumatic stress disorder.

OBJECTIVE: The anterior cingulate cortex (ACC) plays an important role in emotion, and studies in animals have shown changes in ACC structure with early life stress. The purpose of this study was to measure volume of the ACC in PTSD. METHOD: Magnetic resonance imaging (MRI) was used to measure ACC volume in 8 subjects with abuse-related PTSD and 13 healthy subjects without PTSD. ACC volume included Brodmann's area [BA] 24 and 32. RESULTS: Right ACC volume in PTSD patients was significantly smaller than in non-PTSD subjects. CONCLUSION: These results are consistent with smaller ACC volume in PTSD.

Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: a pilot study.

Phenytoin (Dilantin) is an anticonvulsant used in the treatment of epilepsy. It is believed to act by modulation of glutamatergic transmission. Because the neurobiology of post-traumatic stress disorder (PTSD) has been hypothesized to involve alterations in glutamatergic transmission with subsequention neurotoxicity, we assessed the effects of phenytoin on cognition and brain structure in PTSD patients. Phenytoin was administered in an open label fashion for 3 months to nine adult patients with PTSD related to a variety of traumas, including early abuse, combat and car accidents. Subjects underwent magnetic resonance imaging for measurement of whole brain and hippocampal volume, and neuropsychological testing of memory and cognition, before and after treatment. Phenytoin treatment resulted in a significant 6% increase in right brain volume (p < 0.05). Increased hippocampal volume was correlated with reductions in symptom severity as measured by the Clinician Administered PTSD Scale and improvements in executive function as measured by the Trails test. However, treatment associated improvements in memory and cognition did not achieve statistical significance. These findings suggest that phenytoin treatment may be associated with changes in brain structure in patients with PTSD.