Characterizing the experience of auditory verbal hallucinations and accompanying delusions in individuals with a diagnosis of bipolar disorder: A systematic review.

OBJECTIVES: The aim of the current study was to inform ongoing attempts to identify clinically meaningful subcategories of auditory verbal hallucination (AVH), and to evaluate evidence that might pertain to the suitability of current psychological interventions for people with bipolar disorder (BD) who experience psychotic symptoms. METHODS: A comprehensive synthesis of findings on the phenomenology of AVH and delusions in BD is included, alongside a critical review of clinical and cognitive correlates. Studies published in the previous 20 years, until December 2016, were retrieved from the following databases: Embase, CINAHL, MEDLINE, PsycINFO and Web of Science. Thirty-two articles were reviewed after applying a set of predetermined inclusion criteria. RESULTS: Psychotic symptoms were common in both manic and depressive phases, although higher frequencies were indicated in mania. Few detailed characterizations of AVH phenomenology were identified. Delusions with persecutory, grandiose and referential themes were the most common in BD. AVHs were associated with delusions and there was evidence to suggest that delusion subtype may vary according to mood state and type of AVH. Data on clinical correlates of AVH in BD were sparse. However, the results indicated that cognitive appraisals or interpretations of voices might be different in BD from those established to be predictive of clinical outcomes in schizophrenia spectrum disorders. CONCLUSIONS: Clear gaps exist in our current understanding of the first-person experience of AVH in BD and the potential relationship to co-occurring symptoms, including delusions. Further research into cognitive interpretations of AVH in BD might inform adapted psychological interventions for psychotic symptoms in this population.

Impaired verbal self-monitoring in individuals at high risk of psychosis.

BACKGROUND: Cognitive models suggest that auditory verbal hallucinations arise through defective self-monitoring and the external attribution of inner speech. We used a paradigm that engages verbal self-monitoring (VSM) to examine whether this process is impaired in people experiencing prodromal symptoms, who have a very high risk of developing psychosis. METHOD: We tested 31 individuals with an At-Risk Mental State (ARMS) and 31 healthy volunteers. Participants read single adjectives aloud while the source and pitch of the online auditory verbal feedback was manipulated, then immediately identified the source of the speech they heard (Self/Other/Unsure). Response choice and reaction time were recorded. RESULTS: When reading aloud with distorted feedback of their own voice, ARMS participants made more errors than controls (misidentifications and unsure responses). ARMS participants misidentified the source of their speech as 'Other' when the level of acoustic distortion was severe, and misidentification errors were inversely related to reaction times. CONCLUSIONS: Impaired VSM is evident in people with an ARMS, although the deficit seems to be less marked than in patients with schizophrenia. Follow-up of these participants may clarify the extent to which the severity of this impairment predicts the subsequent onset of psychosis and development of positive symptoms.

Neural correlates of visuospatial working memory in the 'at-risk mental state'.

BACKGROUND: Impaired spatial working memory (SWM) is a robust feature of schizophrenia and has been linked to the risk of developing psychosis in people with an at-risk mental state (ARMS). We used functional magnetic resonance imaging (fMRI) to examine the neural substrate of SWM in the ARMS and in patients who had just developed schizophrenia. METHOD: fMRI was used to study 17 patients with an ARMS, 10 patients with a first episode of psychosis and 15 age-matched healthy comparison subjects. The blood oxygen level-dependent (BOLD) response was measured while subjects performed an object-location paired-associate memory task, with experimental manipulation of mnemonic load. RESULTS: In all groups, increasing mnemonic load was associated with activation in the medial frontal and medial posterior parietal cortex. Significant between-group differences in activation were evident in a cluster spanning the medial frontal cortex and right precuneus, with the ARMS groups showing less activation than controls but greater activation than first-episode psychosis (FEP) patients. These group differences were more evident at the most demanding levels of the task than at the easy level. In all groups, task performance improved with repetition of the conditions. However, there was a significant group difference in the response of the right precuneus across repeated trials, with an attenuation of activation in controls but increased activation in FEP and little change in the ARMS. CONCLUSIONS: Abnormal neural activity in the medial frontal cortex and posterior parietal cortex during an SWM task may be a neural correlate of increased vulnerability to psychosis.

Neural correlates of movement generation in the 'at-risk mental state'.

OBJECTIVE: People with 'prodromal' symptoms have a very high risk of developing psychosis. We examined the neurocognitive basis of this vulnerability by using functional MRI to study subjects with an at-risk mental state (ARMS) while they performed a random movement generation task. METHOD: Cross-sectional comparison of individuals with an ARMS (n = 17), patients with first episode schizophreniform psychosis (n = 10) and healthy volunteers (n = 15). Subjects were studied using functional MRI while they performed a random movement generation paradigm. RESULTS: During random movement generation, the ARMS group showed less activation in the left inferior parietal cortex than controls, but greater activation than in the first episode group. CONCLUSION: The ARMS is associated with abnormalities of regional brain function that are qualitatively similar to those in patients who have recently presented with psychosis but less severe.

Effect of spinning on the shape and stability of a pendent drop.

Assuming that we wish to measure the surface tension between two liquids by running a pendent drop experiment, we present calculations supporting the case for spinning the drop. For bridges, jets, etc., spinning a heavy fluid surrounded by a lighter fluid is strictly destabilizing. But we find that spinning a drop may be stabilizing and, if this is so, it leads to larger critical volumes, volumes where stability is lost, and thus more accurate measurements of surface tension. There are two observable patterns, one symmetric and the other unsymmetric, at the point of instability. The symmetric pattern leads to larger critical volumes. Our aim is to show how spinning can be used to achieve the symmetric pattern.

The role of metacognitive beliefs in determining the impact of anomalous experiences: a comparison of help-seeking and non-help-seeking groups of people experiencing psychotic-like anomalies.

BACKGROUND: Current psychological models of psychotic symptoms suggest that metacognitive beliefs impact on an individual's appraisal of anomalous experiences, and thereby influence whether these lead to distress and become clinical symptoms. This study examined the relationship between maladaptive metacognitive beliefs, anomalous experiences, anomaly-related distress, anxiety and depression and diagnostic status. METHOD: The Metacognitions Questionnaire (MCQ), Symptom Checklist 90 - Revised, and Appraisals of Anomalous Experiences interview were administered to 27 people diagnosed with a psychotic disorder, 32 people meeting At Risk Mental State (ARMS) criteria, 24 people with psychotic-like experiences but no need for care, and 32 healthy volunteers. RESULTS: The two clinical groups scored higher than non-patient controls and individuals experiencing psychotic-like anomalies with no need for care on most subscales of the MCQ, particularly the 'general negative beliefs about thoughts' (NEG) subscale. However, most group differences became non-significant when anxiety and depression were controlled for. Few relationships were found between the MCQ subscales and psychotic-like anomalies and anomaly-related distress. Cognitive/attentional difficulty was the only type of anomaly to be significantly associated with maladaptive metacognitive beliefs. Anomaly-related distress was associated with only the NEG subscale of the MCQ. CONCLUSIONS: Maladaptive metacognitive beliefs, as measured by the MCQ, appear to be related more to elevated levels of general psychopathology in psychotic and at-risk groups than to the presence of, and distress associated with, psychotic experiences. Processes by which metacognitions may impact upon the need for care are discussed.

Economic impact of early intervention in people at high risk of psychosis.

BACKGROUND: Despite the increasing development of early intervention services for psychosis, little is known about their cost-effectiveness. We assessed the cost-effectiveness of Outreach and Support in South London (OASIS), a service for people with an at-risk mental state (ARMS) for psychosis. METHOD: The costs of OASIS compared to care as usual (CAU) were entered in a decision model and examined for 12- and 24-month periods, using the duration of untreated psychosis (DUP) and rate of transition to psychosis as key parameters. The costs were calculated on the basis of services used following referral and the impact on employment. Sensitivity analysis was used to test the robustness of all the assumptions made in the model. RESULTS: Over the initial 12 months from presentation, the costs of the OASIS intervention were pound1872 higher than CAU. However, after 24 months they were pound961 less than CAU. CONCLUSIONS: This model suggests that services that permit early detection of people at high risk of psychosis may be cost saving.

Restriction of secretory granule motion near the plasma membrane of chromaffin cells.

We used total internal reflection fluorescence microscopy to study quantitatively the motion and distribution of secretory granules near the plasma membrane (PM) of living bovine chromaffin cells. Within the approximately 300-nm region measurably illuminated by the evanescent field resulting from total internal reflection, granules are preferentially concentrated close to the PM. Granule motion normal to the substrate (the z direction) is much slower than would be expected from free Brownian motion, is strongly restricted over tens of nanometer distances, and tends to reverse directions within 0.5 s. The z-direction diffusion coefficients of granules decrease continuously by two orders of magnitude within less than a granule diameter of the PM as granules approach the PM. These analyses suggest that a system of tethers or a heterogeneous matrix severely limits granule motion in the immediate vicinity of the PM. Transient expression of the light chains of tetanus toxin and botulinum toxin A did not disrupt the restricted motion of granules near the PM, indicating that SNARE proteins SNAP-25 and VAMP are not necessary for the decreased mobility. However, the lack of functional SNAREs on the plasma or granule membranes in such cells reduces the time that some granules spend immediately adjacent to the PM.

Appraisals of Anomalous Experiences Interview (AANEX): a multidimensional measure of psychological responses to anomalies associated with psychosis.

BACKGROUND: Cognitive models of psychosis suggest that whether anomalous experiences lead to clinically relevant psychotic symptoms depends on how they are appraised, the context in which they occur and the individual's emotional response. AIMS: To develop and validate a semi-structured interview (the Appraisals of Anomalous Experiences Interview; AANEX) to assess (a) anomalous experiences and (b) appraisal, contextual and response variables. METHOD: Following initial piloting, construct validity was tested via cross-sectional comparison of data from clinical and non-clinical samples with anomalous experiences. Interrater reliability was also assessed. RESULTS: Scores from AANEX measuring appraisals, responses and social support differentiated the clinical and nonclinical groups. Interrater reliability was satisfactory for 65 of the 71 items. Six items were subsequently amended. CONCLUSIONS: The AANEX is a valid multidimensional instrument that provides a detailed assessment of psychotic-like experiences and subjective variables relevant to the development of a need for clinical care.

Delusion formation and reasoning biases in those at clinical high risk for psychosis.

BACKGROUND: Cognitive models propose that faulty appraisal of anomalous experiences is critical in developing psychosis, particularly delusions. A data gathering bias may be fundamental to abnormal appraisal. AIMS: To examine whether there is a data gathering bias in people at high risk of developing psychosis. METHOD: Individuals with an at-risk mental state (n=35) were compared with a matched group of healthy volunteers (n=23). Participants were tested using a modified version of the 'beads' reasoning task with different levels of task difficulty. RESULTS: When task demands were high, the at-risk group made judgements on the basis of less information than the control group (P<0.05). Within both groups, jumping to conclusions was directly correlated with the severity of abnormal beliefs and intolerance of uncertainty (P<0.05). In the at-risk group it was also associated with impaired working memory (P<0.05), whereas in the control group poor working memory was associated with a more conservative response style (P<0.05). CONCLUSIONS: People with an at-risk mental state display a jumping to conclusions reasoning style, associated with impaired working memory and intolerance of uncertainty. This may underlie a tendency to develop abnormal beliefs and a vulnerability to psychosis.

Ecological validity of measures of executive functioning.

OBJECTIVES: This study aimed to ascertain the ecological validity of the Hayling and Brixton tests of executive functioning, by investigating whether cognitive 'impairment' detected by these measures was associated with assessment of 'disability' and 'handicap'. DESIGN AND METHOD: A correlational design was employed to evaluate the degree of association between the executive test results, and behavioural and community integration measures. Participants were 53 people with brain injuries participants who were selected from neuropsychology patient lists and their 'significant other'. The brain-injured participant was given the executive tests, together with behavioural and community integration questionnaires, while their 'significant other' was given an equivalent behavioural questionnaire and structured interview. RESULTS: There were moderate relationships between scores on the tests and measures of everyday functioning, suggesting that the tests have modest ecological validity. CONCLUSIONS: The tests contribute to understanding the impact of executive impairment on everyday functioning, but they should be interpreted in combination with other measures of executive functioning.

Misattributing speech and jumping to conclusions: a longitudinal study in people at high risk of psychosis.

Biases in cognition such as Jumping to Conclusions (JTC) and Verbal Self-Monitoring (VSM) are thought to underlie the formation of psychotic symptoms. This prospective study in people with an At Risk Mental State (ARMS) for psychosis examined how these cognitive biases changed over time, and predicted clinical and functional outcomes. Twenty-three participants were assessed at clinical presentation and a mean of 31 months later. Performance on a JTC and VSM tasks were measured at both time points. Relationships to symptom severity, level of function and the incidence of psychotic disorder were then examined. The levels of symptoms, function and VSM all improved over time, while JTC was stable. Five participants (22%) developed a psychotic disorder during the follow-up period, but the risk of transition was not related to performance on either task at baseline, or to longitudinal changes in task performance. JTC performance correlated with symptom severity at baseline and follow-up. Similarly, performance on the two tasks was not related to the level of functioning at follow-up. Thus, while the ARMS is associated with both VSM and JTC biases, neither predict the onset of psychosis or the overall functional outcome.

Vasospasm in monkeys resolves because of loss of and encasement of subarachnoid blood clot.

BACKGROUND AND PURPOSE: We studied in monkeys why vasospasm resolves after subarachnoid hemorrhage (SAH). METHODS: Monkeys underwent angiography and right (n=17) or bilateral (n=8) SAH. Animals with bilateral SAH underwent angiography 1, 3, 5, and 7 days later. Animals with right SAH underwent angiography 7 days later. The clot was then not removed (n=5), removed and replaced with fresh clot (n=7), or removed and not replaced (n=5). At the same time on day 7, the removed clot (n=12) or fresh clot (n=5) was placed on the left side. Angiography was repeated every 2 days until day 14. RESULTS: SAH caused significant vasospasm on day 7 that resolved by day 14. Removal of clot on day 7 resulted in more rapid resolution of vasospasm. Placement of fresh clot onto arteries that had already been exposed to clot for 7 days produced vasospasm that persisted without resolving for an additional 7 days. Placement of 7-day-old clot from the right onto previously unexposed left arteries or of clot from blood removed from an animal 7 days after SAH caused significantly more rapid onset of vasospasm compared with de novo vasospasm. Microscopic examination of the clots showed they were surrounded by macrophages 7 days after SAH. Arterial compliance and contractility were reduced in relation to duration of the exposure of arteries to clot. CONCLUSIONS: Vasospasm resolves because of loss of subarachnoid blood clot. We hypothesize that reduced spasmogen release from the clot contributes to resolution of vasospasm. There was no response in the cerebral arteries that rendered them less responsive to the subarachnoid clot.

Heme oxygenase-1 and ferritin are increased in cerebral arteries after subarachnoid hemorrhage in monkeys.

Hemoglobin is a key factor in the production of cerebral vasospasm. Metabolism of hemoglobin involves breakdown of heme by heme oxygenase (HO) and sequestration of the released iron in ferritin. We determined whether subarachnoid hemorrhage induces these proteins in cerebral arteries and, if so, in which cells they are produced. Whether the changes correlated with vasospasm also was investigated. Subarachnoid hemorrhage was created in monkeys, and vasospasm was assessed by angiography in cohorts of animals killed 3, 7, or 14 days after the hemorrhage. Ferritin and HO-1 messenger ribonucleic acid (mRNA) and protein were measured by competitive reverse transcription-polymerase chain reaction and Western blotting in hemorrhage-side and control-side cerebral arteries and brain tissue. The location of these proteins was determined by immunohistochemistry. There was significant vasospasm 3 and 7 days but not 14 days after subarachnoid hemorrhage. There were no significant changes in mRNA for HO-1 or ferritin in cerebral arteries or brain tissue at any time. There was a significant increase in HO-1 and ferritin protein in hemorrhage-side compared with control-side cerebral arteries at 3, 7, and 14 days. The increase in HO-1 protein was maximal at 3 days, whereas the increase in ferritin protein was maximal at 7 days. There was no detectable increase in HO-1 or ferritin protein in brain tissue at any time. Immunohistochemistry localized HO-1 protein and ferritin to cells in the adventitia of the arterial wall. We show that subarachnoid hemorrhage is associated with a significant increase in HO-1 and ferritin proteins in cerebral arteries that begins at least as early as 3 days after the hemorrhage and that persists for up to 14 days.

Experimental allergic encephalomyelitis: neutralizing antibody to TGF beta 1 enhances the clinical severity of the disease.

Experimental allergic encephalomyelitis (EAE) is a well established model for the human autoimmune disease multiple sclerosis. Recently, we and others have shown that the administration of TGF beta is therapeutically effective in reducing incidence and severity of EAE. Here we show that the addition of anti-TGF beta 1 to myelin basic protein (MBP)-activated lymph node cells enhance the T cell proliferative response by 28% in vitro and in vivo and that injections of anti-TGF beta 1 antibody worsen EAE both in incidence and severity. Further, an inverse relationship was observed in the amount of IL-2 and TGF beta detected in MBP stimulated culture supernatants. We show that IL-2 decreases from 248 U/ml at 48 h to non-detectable at 96 h, while TGF beta increases from 0.5 ng/ml to 1.2 ng/ml, respectively. These observations further indicate a role for endogenous TGF beta 1 in the immunoregulation of EAE.

Cerebral blood flow in sickle cell cerebrovascular disease.

Cerebral blood flow (CBF) has been studied by the xenon-133 (133Xe) inhalation method in 16 children with suspected sickle cell cerebrovascular disease. Abnormalities consisting of decreases in total, hemispheral, or regional CBF were found in 17 of 26 studies. Eleven studies performed immediately after stroke, transient ischemic attack, or depression of state of alertness showed abnormalities. In addition to confirming regional cerebrovascular insufficiency in children with stroke due to major cerebral artery occlusion, the method detected diffuse decrease in CBF in children with stupor, coma, and seizures who had normal angiographic findings. In contrast, six of seven studies obtained after exchange transfusion or during maintenance on hypertransfusion therapy showed normal findings. The difference between results in patients with acute neurologic disturbances and those receiving transfusion therapy was statistically significant (P less than .005). The data indicate that the 133Xe method reliably demonstrates cerebrovascular impairment in sickle cell disease. They also suggest that CBF changes in patients with sickle cell disease can be reversed by exchange transfusion and by hypertransfusion therapy. The 133Xe CBF method may be useful for following up children with sickle cell disease who are at high risk for recurrent stroke.

Effect of lipid peroxidation inhibition on retinal ganglion cell death.

PURPOSE: To determine whether the lipid peroxidation inhibitor tirilazad mesylate can block the death of retinal ganglion cells induced by the inhibition of oxidative phosphorylation and glycolysis. METHODS: Rat retinal ganglion cells were labeled retrogradely with the fluorescent tracer DiI, and mixed cultures were prepared. Cell death was induced with chemical hypoxia, hypoglycemia, or glycolysis inhibition, and the effect on cell survival of tirilazad mesylate was assessed. RESULTS: Tirilazad mesylate enhanced relative ganglion cell survival after plating, with detectable effects at 200 nM and a maximal increase above diluent control of 148% +/- 2% at 20 microM. Relative survival at 24 hours in the presence of the complex IV inhibitor sodium cyanide (3 mM) was significantly greater when it was co-incubated with tirilazad mesylate than with diluent control (91.8% +/- 4.6% versus 39.3% +/- 7.1%; P = 0.008). Enhanced relative survival with tirilazad mesylate also was seen in cultures containing reduced glucose media. CONCLUSIONS: The lipid peroxidation blocker tirilazad mesylate inhibits retinal ganglion cell death in vitro. Because irreversible loss of retinal ganglion cells is the final common pathway in a variety of optic neuropathies, this or similar agents may be useful in animal models of optic neuropathies.

Clinical evaluation of intravenous labetalol for the treatment of hypertensive urgency.

Antihypertensive medications currently used in the treatment of hypertensive urgencies are limited due to deleterious side effects or requirements for sophisticated monitoring techniques. Labetalol HCl (Trandate) is a unique adrenergic blocking agent that can smoothly lower blood pressure following bolus injection without increasing heart rate or cardiac output. This study evaluates the efficacy and safety of intravenous boluses of labetalol HCl in the treatment of patients presenting to the hospital with a diagnosis of hypertensive urgency (diastolic blood pressure greater than or equal to 110 mm Hg). After baseline blood pressure and heart rate were recorded, 20 consecutive patients were treated with an initial 20-mg bolus of labetalol. Additional boluses of 40, 80, and 160 mg were administered at least 10 minutes apart in a step-wise fashion until control of blood pressure (diastolic blood pressure less than 100 mm Hg) was achieved or a total of 300 mg had been given. Blood pressures and heart rates were recorded at the time of response or following the last dose of labetalol. Mean (+/- SEM) supine systolic blood pressure decreased from 185 +/- 3 to 155 +/- 4 mm Hg (P less than 0.05) following labetalol therapy, and mean supine diastolic pressure decreased from 120 +/- 2 to 98 +/- 2 mm Hg (P less than 0.05). Mean heart rate did not change significantly. Eighteen of the 20 patients exhibited a therapeutic response; nine patients received a total of 20 mg, six required 60 mg, two required 140 mg, one received 300 mg. Of the two patients who did not respond, one received the maximum dose (300 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Increased cerebral blood flow after external carotid artery revascularization.

Ten patients with symptoms of cerebral ischemia were found to have totally occluded internal carotid arteries with significant external carotid artery stenosis or occlusion. Eight patients underwent external carotid endarterectomy, and two patients underwent saphenous vein bypass to the external carotid artery from the subclavian artery. Cerebral blood flow was measured with 133Xe in six patients preoperatively and in five postoperatively. Four of the six patients had diminished mean flow on the affected side, and three had diminished flow in the contralateral side. All patients had abnormalities in regional cerebral blood flow. Postoperatively, all patients had significant improvement in mean blood flow on the side treated with operation (15% to 39%), and four had improvement of blood flow on the contralateral side (12% to 52%). All had improvement in regional cerebral blood flow. Nine of the 10 patients were relieved of their symptoms. One patient, despite improvement in cerebral blood flow, continued to have diminished cerebral flow and symptoms postoperatively. Subsequent extracranial-intracranial bypass relieved his symptoms and his cerebral blood flow returned to normal. Thus external carotid artery revascularization is effective in increasing total and regional cerebral blood flow and in relieving symptoms of internal carotid artery occlusion and external carotid stenosis. Cerebral blood flow measurement with 133Xe is useful in preoperative patient selection and objective assessment of operative results.

Leaky intra-acinar arteries in rat lungs perfused with hydrogen peroxide.

We have investigated the effects of H2O2 (150 or 300 microM) on the ultrastructure and permeability of the pulmonary endothelium in rat lungs perfused for 60 min with buffered Hanks' bovine serum albumin medium. In one group of experiments, we examined the effect of H2O2 on the uptake and transport of cationized ferritin (CF) by endothelial cells in intra-acinar arteries, alveolar capillaries, and interlobular veins. The influence of the oxidant on endothelial adsorptive endocytic processes was assessed by measuring the density of ferritin particles in luminal vesicles, multivesicular bodies, and basal lamina. In a second group of experiments, we examined the effects of H2O2 on the fine structure and permeability to electron-dense macromolecules of arterial, microvascular, and venous endothelium. For this purpose, at the end of the 60-min perfusion with H2O2, CF was perfused to identify leaky vessels. We found that H2O2 caused a dose-dependent inhibition of transcytosis of CF in all vascular segments. At the lower dose of H2O2, inhibition of transcytotic activity was not associated with structural injury to the vascular endothelium or with elevation of wet-to-dry ratios. At the higher oxidant dose, inhibition of transcytosis was associated with leaky arterial endothelium and elevation of wet-to-dry ratios (6.44 +/- 0.12 vs. 5.64 +/- 0.16, P less than 0.02). The effects of H2)2 were prevented by adding catalase to the perfusate. The selective loss of structural integrity and leakiness of the arterial endothelium were diminished but not completely abolished by perfusing the oxidant retrograde from the venous side.(ABSTRACT TRUNCATED AT 250 WORDS)