Identifying canonical and replicable multi-scale intrinsic connectivity networks in 100k+ resting-state fMRI datasets.

Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

Arterial stiffness assessment in obese black South African patients.

INTRODUCTION: Increased arterial stiffness is a determinant of cardiovascular mortality and an independent marker of cardiovascular disease. The objective of this study was to asses arterial elasticity by determination of pulse-wave velocity (PWV) and augmentation index (Aix) in obese black patients. METHODS: PWV and Aix were assessed non-invasively using the AtCor SphygmoCor® system (AtCor Medical, Inc, Sydney, Australia). The study participants were divided into four groups; healthy volunteers (HV) (n = 29), patients with concomitant diseases but normal body mass index (Nd) (n = 23), obese patients without concomitant diseases (OB) (n = 29) and obese patients with concomitant diseases (OBd) ( n = 29). RESULTS: The difference in the mean levels of PWV was statistically significant in the obese group with and without concomitant disease. The PWV in the OB group (7.9 ± 2.9 m/s) and in the OBd group (9.2 ± 4.4 m/s) was, respectively, 19.7 and 33.3% higher than in the HV group (6.6 ± 2.1 m/s). PWV was directly correlated with age, glycated haemoglobin level, aortic systolic blood pressure and heart rate. The risk of cardiovascular diseases in the obese patient without additional diseases was increased by 50.7%. The presence of concomitant diseases (type 2 diabetes mellitus and hypertension) in addition to obesity increased arterial stiffness by a further 11.4% and therefore also increased the risk of cardiovascular diseases by a further 35.1%. Aix was increased in the OBd and Nd groups by 8.2 and 16.5%, respectively, however the increase was not statistically significant. Aix was directly correlated with age, heart rate and aortic systolic blood pressure. CONCLUSIONS: The obese black patients had a higher PWV, indicating increase in arterial stiffness and therefore a higher risk for cardiovascular disease. In addition, aging, increased blood pressure and type 2 diabetes mellitus contributed further to arterial stiffening in these obese patients.

Important pharmacogenomic aspects in the management of HIV/AIDS

In managing HIV/AIDS with highly active antiretroviral agents, the historical therapeutic aim remains to maintain the plasma concentrations at a level above the half maximal inhibitory concentration (IC50) required for 50% inhibition in viral replication. Concentration dependent toxicity is often observed in patients with elevated drug exposure and high peak plasma levels in lieu accurately calculated drug dosages. Similarly low plasma concentrations are frequently witnessed in individuals receiving adequate dosage regimens. Pharmacogenetic variations in drug metabolizing enzymes may contribute to this phenomenon. Over the last decade, knowledge about the role of pharmacogenetics in the treatment and prediction of ARV plasma levels have increased significantly. However, the extent of these genetic variations remain largely unknown in the South African population,which has sparked a renewed enthusiasm for local pharmacogenetic studies

Important pharmacogenomic aspects in the management of HIV/AIDS

In managing HIV/AIDS with highly active antiretroviral agents, the historical therapeutic aim remains to maintain the plasma concentrations at a level above the half maximal inhibitory concentration (IC50) required for 50% inhibition in viral replication.Concentration dependent toxicity is often observed in patients with elevated drug exposure and high peak plasma levels in lieu of accurately calculated drug dosages. Similarly lowplasmaconcentrationsarefrequently witnessed in individuals receiving adequate dosage regimens. Pharmacogenetic variations in drug metabolizing enzymes may contribute to this phenomenon.Over the last decade, knowledge about the role of pharmacogenetics in the treatment and prediction of ARV plasma levels have increased significantly. However, the extent of these genetic variations remain largely unknown in the South African population,which has sparked a renewed enthusiasm forlocalpharmacogenetic studies

To clot, or not to clot ­ Antithrombotic therapy is the question

Haemostasis and thrombosis rely on three components namely the vascular endothelial wall, blood platelets and the coagulation cascade. Non-physiologic excessive thrombosis occurs when haemostatic processes are dysfunctional, causing undue clot formation or reduced clot lysis. Antithrombotic agents including antiplatelet, anticoagulation and fibrinolytic agents are essential for the prophylaxis and pharmacological management of venous thromboembolism and arterial thrombosis. Anticoagulation treatment options have expanded steadily over the past few decades, providing a greater number of agents. Anticoagulants that directly target the enzymatic activity of thrombin and factor Xa have recently been developed to address the inadequacies of traditional vitamin K antagonists. Appropriate use of these agents requires knowledge of their individual characteristics, risks, and benefits

Complexity in mood disorder diagnosis: fMRI connectivity networks predicted medication-class of response in complex patients.

OBJECTIVE: This study determined the clinical utility of an fMRI classification algorithm predicting medication-class of response in patients with challenging mood diagnoses. METHODS: Ninety-nine 16-27-year-olds underwent resting state fMRI scans in three groups-BD, MDD and healthy controls. A predictive algorithm was trained and cross-validated on the known-diagnosis patients using maximally spatially independent components (ICs), constructing a similarity matrix among subjects, partitioning the matrix in kernel space and optimizing support vector machine classifiers and IC combinations. This classifier was also applied to each of 12 new individual patients with unclear mood disorder diagnoses. RESULTS: Classification within the known-diagnosis group was approximately 92.4% accurate. The five maximally contributory ICs were identified. Applied to the complicated patients, the algorithm diagnosis was consistent with optimal medication-class of response to sustained recovery in 11 of 12 cases (i.e., almost 92% accuracy). CONCLUSION: This classification algorithm performed well for the know-diagnosis but also predicted medication-class of response in difficult-to-diagnose patients. Further research can enhance this approach and extend these findings to be more clinically accessible.

Commercial herbal medicines used as African traditional medicines: Ngoma Herbal Tonic Immune Booster interferes with a rapid urine drug screening test.

BACKGROUND: The prevalent use of African traditional medicine by the general public has been reported. With commercialisation and marketing, some of the herbal medicines (HMs) used are readily available over the counter, most of them promoted as immune boosters. These commercial HMs have not been taken through clinical trials and other tests that would validate their composition and safety, and other properties such as their effect on laboratory diagnostic tests. OBJECTIVE: To investigate the cross-reactivity of selected HMs with commonly tested drugs of abuse (DoA) using a qualitative rapid urinalysis assay. METHODS: The six HMs selected were bought from local pharmacies. A rapid urinalysis screening test was performed with the Instant View Multi-Drug of Abuse Test kit from Labstix Diagnostics. Drug-free urine (DFU) was pooled from samples donated by healthy volunteers. Urine samples that had tested positive for DoA were obtained from a pharmacology laboratory. Aliquots of the urine samples were spiked with the HMs in neat and diluted form, and tested at various time intervals. RESULTS: The results for the DFU samples spiked with the HMs remained negative. There were no significant changes in pH or specific gravity of the samples. The results of samples that had tested positive for tetrahydrocannabinol (THC) were not altered by five of the HMs when spiked at 40% v/v. The HM Ngoma Herbal Tonic Immune Booster caused false-negative results for the THC test. CONCLUSION: An important finding is that the herbal mixture Ngoma Herbal Tonic Immune Booster caused false-negative results for the cannabinoid screening test. It adds to the list of substances that may be potential adulterants of urine for screening tests.

Depression, marijuana use and early-onset marijuana use conferred unique effects on neural connectivity and cognition.

OBJECTIVE: Marijuana (MJ) use is common. Research shows risks for psychiatric illnesses, including major depressive disorder (MDD) and cognitive deficits with MJ use, particularly early-onset use. We investigated cognitive function, functional connectivity, and genetic risk with MDD alone and combined with MJ use, and differences between early-vs. late-onset/non-MJ use in youth. METHOD: A total of 74 youth in four groups were studied: healthy control, MDD, frequent MJ use and current/past MDD plus frequent MJ use. Psychiatric symptoms, cognitive performance and demographics were measured. Default mode network (DMN) brain connectivity was determined. Risk alleles in six genes of interest were evaluated. RESULTS: DMN differences among groups in reward-processing and motor control regions were found; the effects of MJ use and MDD were distinct. Early-onset MJ use was associated with lower IQ and hyperconnectivity within areas of the DMN. Early-onset MJ use was associated with the BDNF risk allele. CONCLUSIONS: Cognitive deficits linked with early-onset MJ use were present within several years after MJ use began and may result from, predispose to, or share a common cause with early-onset MJ use. The DMN was affected by MDD, MJ and their combination, as well as by early-onset MJ use. BDNF carrier state may predispose to early-onset MJ use.

Post-dexamethasone cortisol correlates with severity of depression before and during carbamazepine treatment in women but not men.

OBJECTIVE: Previous studies show a state-dependent relationship between depression and post-dexamethasone suppression test (DST) cortisol level, as well as differences in DST response with age and gender. METHOD: In this study, 74 research in-patients with affective disorders were given the DST on placebo and in a subgroup following treatment with carbamazepine. Depression was evaluated twice daily with the Bunney-Hamburg (BH) rating scale. Data were examined for the total subject population, by gender and by menopausal status in women. RESULTS: A robust positive correlation was observed between depression severity and post-DST cortisol in pre- and postmenopausal females, but not in males. This relationship persisted in women when restudied on a stable dose of carbamazepine (n=42). CONCLUSION: The pathophysiological implications of this selective positive relationship between severity of depression and post-DST cortisol in women, but not men, should be explored further.

Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder.

BACKGROUND: Nuclear imaging studies have examined cerebral blood flow (rCBF) in subjects with posttraumatic stress disorder (PTSD) using symptom evocation paradigms. To date, no such studies have investigated rCBF as related to subjects' reports of flashback intensity. METHODS: Subjects with varying traumatic histories and longstanding PTSD were studied using [15O]-H2O positron emission tomography with an auditory script of their traumatic event. Eight subjects had three resting scans followed by their script and additional scans. Heart rate responses as well as the presence of flashbacks and their intensity were recorded. rCBF was correlated with flashback intensity in each subject's scan. Combined analysis of all subjects' data yielded common regions related to the flashback experience. RESULTS: rCBF correlated directly with flashback intensity in the brainstem, lingula, bilateral insula, right putamen and left hippocampal and perihippocampal, somatosensory and cerebellar regions. Inverse correlations with rCBF were found in bilateral dorsolateral prefrontal, right fusiform and right medial temporal cortices. CONCLUSIONS: This study correlated flashback intensity and rCBF in a group of patients with chronic PTSD suggesting involvement of brainstem, and areas associated with motor control, complex visual/spatial cues and memory.

A placebo-controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders.

There is a pressing need for additional treatment options for refractory mood disorders. This controlled comparative study evaluated the efficacy of lamotrigine (LTG) and gabapentin (GBP) monotherapy versus placebo (PLC). Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind, randomized, crossover series of three 6-week monotherapy evaluations including LTG, GBP, and PLC. There was a standardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose (LTG 500 mg or GBP 4,800 mg). The primary outcome measure was the Clinical Global Impressions Scale (CGI) for Bipolar Illness as supplemented by other standard rating instruments. The mean doses at week 6 were 274 +/- 128 mg for LTG and 3,987 +/- 856 mg for GBP. Response rates (CGI ratings of much or very much improved) were the following: LTG, 52% (16/31); GBP, 26% (8/31); and PLC, 23% (7/31) (Cochran's Q = 6.952, df = 2, N = 31, p = 0.031). Post hoc Q differences (df = 1, N = 31) were the following: LTG versus GBP (Qdiff = 5.33, p = 0.011); LTG versus PLC (Qdiff = 4.76, p = 0.022); and GBP versus PLC (Qdiff = 0.08, p = 0.70). With respect to anticonvulsant dose and gender, there was no difference between the responders and the nonresponders. The agents were generally well tolerated. This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients. Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study.

Regional cerebral metabolism associated with anxiety symptoms in affective disorder patients.

BACKGROUND: We studied the relationship between regional cerebral metabolism and the severity of anxiety in mood disorder patients, controlling for depression severity. METHODS: Fifty-two medication-free patients with unipolar or bipolar illness underwent positron emission tomography with [(18)F]-fluorodeoxyglucose. Hamilton Depression Rating Scale and Spielberger Anxiety-State Scale scores were obtained for the week of the scan. Analyses were performed on globally normalized images and were corrected for multiple comparisons. RESULTS: After covarying for depression scores, age, and gender, Spielberger Anxiety-State Scale scores correlated directly with regional cerebral metabolism in the right parahippocampal and left anterior cingulate regions, and inversely with metabolism in the cerebellum, left fusiform, left superior temporal, left angular gyrus, and left insula. In contrast, covarying for anxiety scores, age, and gender, Hamilton Depression Rating Scale scores correlated directly with regional cerebral metabolism in the bilateral medial frontal, right anterior cingulate, and right dorsolateral prefrontal cortices. CONCLUSIONS: Comorbid anxiety symptoms are associated with specific cerebral metabolic correlates that partially overlap with those in the primary anxiety disorders and differ from those associated with depression severity.

Emerging trends in the treatment of rapid cycling bipolar disorder: a selected review.

Recent evidence suggests that lithium therapy (even as supplemented by antidepressants and neuroleptics) is inadequate for the majority of patients with bipolar illness, and particularly those with rapid cycling. Valproate and carbamazepine have emerged as adjuncts and alternatives, but they, too, often require additional approaches with lithium, thyroid hormones, and other putative mood stabilizers, including nimodipine (and related dihydropyridine calcium channel blockers), lamotrigine, gabapentin, topiramate, and the atypical neuroleptics. Evaluating how these agents and the unimodal antidepressants are optimally applied and sequenced in the treatment of bipolar illness with its multiple subtypes, patterns and comorbidities will require much future investigation and the development of new methodological clinical trial approaches.

CSF thyrotropin-releasing hormone gender difference: implications for neurobiology and treatment of depression.

In light of the postulated role of thyrotropin-releasing hormone (TRH) as an endogenous anti-depressant, 56 refractory mood-disordered patients and 34 healthy adult control subjects underwent lumbar puncture for cerebrospinal fluid (CSF) TRH analysis. By two-way analysis of variance, there was no difference between CSF TRH in patients (as a group or by diagnostic subtype) and control subjects (n = 90, F = 0.91, df = 2.84, P = 0.41). There was, however, a CSF TRH gender difference (females, 2.95 pg/ml; males, 3.98 pg/ml; n = 90, F = 4.11, df = 1.84, P < 0.05). A post hoc t-test revealed the greatest gender difference in the bipolar group (t = 2.52, P < 0.02). There was no significant difference in CSF TRH in "ill" vs. "well" state (n = 20, P = 0.41). The role of elevated levels of CSF TRH in affectively ill men--or the role of decreased levels of CSF TRH in affectively ill women--remains to be investigated but could be of pathophysiological relevance.

Repetitive transcranial magnetic stimulation as a neuropsychiatric tool: present status and future potential.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising therapeutic intervention in the treatment of affective disorders. The differences in the type of electrical stimulation required for therapeutic efficacy by rTMS and electroconvulsive therapy (ECT) are discussed. In contrast to ECT, rTMS would not appear to require the generation of a major motor seizure to achieve therapeutic efficacy. Accordingly, it carries the potentially important clinical advantages of not requiring anesthesia and of avoiding side effects such as transient memory loss. Preclinical studies on long-term potentiation (LTP) and long-term depression (LTD) in hippocampal and amygdala slices, as well as clinical data from neuroimaging studies, have provided encouraging clues for potential frequency-dependent effects of rTMS. Preliminary evidence from position emission tomography (PET) scans suggests that higher frequency (20 Hz) stimulation may increase brain glucose metabolism in a transsynaptic fashion, whereas lower frequency (1 Hz) stimulation may decrease it. Therefore, the ability of rTMS to control the frequency as well as the location of stimulation, in addition to its other advantages, has opened up new possibilities for clinical explorations and treatments of neuropsychiatric conditions.

Frequency dependence of antidepressant response to left prefrontal repetitive transcranial magnetic stimulation (rTMS) as a function of baseline cerebral glucose metabolism.

BACKGROUND: Recent studies suggest that both high frequency (10-20 Hz) and low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) have an antidepressant effect in some individuals. Electrophysiologic data indicate that high frequency rTMS enhances neuronal firing efficacy and that low frequency rTMS has the opposite effect. METHODS: We investigated the antidepressant effects of 10 daily left prefrontal 1 Hz versus 20 Hz rTMS with the hypothesis that within a given subject, antidepressant response would differ by frequency and vary as a function of baseline cerebral glucose metabolism. After baseline PET scans utilizing [18F]-Fluorodeoxyglucose, thirteen subjects participated in a randomized crossover trial of 2 weeks of 20 Hz paired with 2 weeks 1 Hz or placebo rTMS. RESULTS: We found a negative correlation between degree of antidepressant response after 1 Hz compared to 20 Hz rTMS (r = -0.797, p < .004). Additionally, better response to 20 Hz was associated with the degree of baseline hypometabolism, whereas response to 1 Hz rTMS tended to be associated with baseline hypermetabolism. CONCLUSIONS: These preliminary results suggest that antidepressant response to rTMS might vary as a function of stimulation frequency and may depend on pretreatment cerebral metabolism. Further studies combining rTMS and functional neuroimaging are needed.

The motivations for self-injury in psychiatric inpatients.

Nonsuicidal self-injurious behavior (SIB) occurs in both culturally appropriate and culturally inappropriate forms. It is one of the diagnostic criteria for borderline personality disorder, but it occurs in several psychiatric and neurological populations. The personal intent of SIB in psychiatric populations is incompletely understood. A self-report scale (Self-Injury Motivation Scale; SIMS) to assess motivation for self-injury was developed. Relationships among motivation for SIB, characteristics of SIB, and psychopathology were explored. A semistructured interview and the SIMS, Dissociative Experiences Scale, Beck Depression Inventory, Davidson Trauma Scale, and Millon Clinical Multiaxial Inventory-II were given to 99 consecutively admitted inpatients. The SIMS had good reliability and validity. A high SIMS score suggested distinct psychopathology. Several factors on the SIMS differentiated motivations for SIB. Patients with different SIMS factor profiles had different psychopathology.

A history of the use of anticonvulsants as mood stabilizers in the last two decades of the 20th century.

Anticonvulsants have moved into an important position as alternatives and adjuncts to lithium carbonate in the treatment of bipolar illness. Work with the nonhomologous model of kindled seizures helped in the choice of carbamazepine as a potential mood stabilizer and in the study of the mechanisms of action of the second generation anticonvulsants carbamazepine and valproate, as well as the putative third generation psychotropic anticonvulsants lamotrigine and gabapentin. Anticonvulsant neuropeptides such as TRH and nonconvulsant approaches with repeated transcranial magnetic stimulation (rTMS) also appear promising.

Neural plasticity and emotional memory.

Posttraumatic stress disorder is the pathological replay of emotional memory formed in response to painful, life-threatening, or horrifying events. In contrast, depression is often precipitated by more social context-related stressors. New data suggest that different types of life experiences can differentially impact biochemistry, physiology, anatomy, and behavior at the level of changes in gene expression. Repeated separation of neonatal rat pups from their mother results in many long-lasting alterations in biology and behavior paralleling that in depression, including hypercortisolism. The role of the amygdala in modulating emotional memory is highlighted, as well as some of its unique properties such as metaplasticity (i.e., the differential direction of long-term adaptation, either potentiation or depression) in response to the same input as a function of the prior history of stimulation. The implications of these emerging data on the physiological and molecular mechanisms underlying emotional memory emphasize the particular importance of prevention and early intervention.