DSpace Academic/Research Unit: Psychiatry

Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the Two Hit Hypothesis for the Development of Schizophrenia

2012-07-09T09:13:38Z

Title: Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the Two Hit Hypothesis for the Development of Schizophrenia Author: DALTON, VICTORIA Abstract: Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia. Description: PUBLISHED

DUNDRUM-D: Developmental Understanding of Drug Misuse & Dependence (Short version)

2012-07-05T03:21:06Z

Title: DUNDRUM-D: Developmental Understanding of Drug Misuse & Dependence (Short version) Author: KENNEDY, HARRY Abstract: This is the short version of the Developmental Understanding of Drug Misuse and Dependence DUNDRUM-D. DUNDRUM-D is an instrument which has grown out of the series of prison psychiatric morbidity studies carried out by the National Forensic Mental Health Service in the population of the Irish Prison Service. The DUNDRUM-D is distinguished from other screening and diagnostic instruments by the developmental perspective it takes on life time careers of substance use, misuse and dependence. We recognise that those with substance misuse problems commonly begin using intoxicants such as solvents very early, typically before the age of 12 and progress through other substances as they get older and are able to access more expensive intoxicants. Some will have patterns of binge use, others are continuously intoxicated. Some will use only one or two substances of choice; others will use many different types of drug almost indiscriminately. It is not uncommon for a person to make the transition from dependence on one drug to substitution for another, followed some time later by further changes in type of intoxicant or pattern of use. All such patterns shift and change over time, and recovery is always possible. Indeed spontaneous recovery is the most common outcome for most substance misuse problems. The purpose of this form of instrument is to record these patterns as an exercise in contemplation for those who are not yet at the contemplative stage or recovery. While questions are asked about harmful use and abuse, these are deliberately reserved until towards the end of the interview. We believe the regular use of this instrument is also a way of learning from one's patients/clients. The substances used, the language, patterns and practices of use all change constantly and rapidly from month to month and from city to city. We have found that this instrument can be used in its short form as a screening tool e.g. with the SADS-L or with the CAARMS. In forensic mental health practice, it is 'substance abuse' as defined in the DSM system that is the best guide to harmful use. The form of the instrument lends itself to the assessment of other problem behaviours such as gambling, binging and purging food, and repetitive self-harm to relieve tension (e.g. cutting). The DUNDRUM-D can be used by any professionally qualified clinician. Description: PUBLISHED

DUNDRUM-D: Developmental Understanding of Drug Misuse & Dependence

2012-07-27T10:58:03Z

Title: DUNDRUM-D: Developmental Understanding of Drug Misuse & Dependence Author: KENNEDY, HARRY Abstract: Developmental Understanding of Drug Misuse and Dependence DUNDRUM-D This instrument has grown out of the series of prison psychiatric morbidity studies carried out by the National Forensic Mental Health Service in the population of the Irish Prison Service. The DUNDRUM-D is distinguished from other screening and diagnostic instruments by the developmental perspective it takes on life time careers of substance use, misuse and dependence. We recognise that those with substance misuse problems commonly begin using intoxicants such as solvents very early, typically before the age of 12 and progress through other substances as they get older and are able to access more expensive intoxicants. Some will have patterns of binge use, others are continuously intoxicated. Some will use only one or two substances of choice; others will use many different types of drug almost indiscriminately. It is not uncommon for a person to make the transition from dependence on one drug to substitution for another, followed some time later by further changes in type of intoxicant or pattern of use. All such patterns shift and change over time, and recovery is always possible. Indeed spontaneous recovery is the most common outcome for most substance misuse problems. The purpose of this form of instrument is to record these patterns as an exercise in contemplation for those who are not yet at the contemplative stage or recovery. While questions are asked about harmful use and abuse, these are deliberately reserved until towards the end of the interview. We believe the regular use of this instrument is also a way of learning from one's patients/clients. The substances used, the language, patterns and practices of use all change constantly and rapidly from month to month and from city to city. We have found that this instrument can be used in its short form as a screening tool e.g. with the SADS-L or with the CAARMS. In forensic mental health practice, it is 'substance abuse' as defined in the DSM system that is the best guide to harmful use. The form of the instrument lends itself to the assessment of other problem behaviours such as gambling, binging and purging food, and repetitive self-harm to relieve tension (e.g. cutting). The DUNDRUM-D can be used by any professionally qualified clinician. Description: PUBLISHED

A comparison of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour

2012-06-27T09:32:46Z

Title: A comparison of brief pulse and ultrabrief pulse electroconvulsive stimulation on rodent brain and behaviour Author: MC LOUGHLIN, DECLAN; O'MARA, SHANE MICHAEL; O'DONOVAN, SINEAD Abstract: Brief pulse electroconvulsive therapy (BP ECT; pulse width 0.5-1.5 msec) is a very effective treatment for severe depression but is associated with cognitive side-effects. It has been proposed that ultrabrief pulse (UBP; pulse width 0.25-0.30 msec) ECT may be as effective as BP ECT but have less cognitive effects because it is a more physiological form of neuronal stimulation. To investigate this further, we treated normal rats with a 10 session course of either BP (0.5 msec), UBP (0.3 msec), or sham electroconvulsive stimulation (ECS) and measured antidepressant-related changes in dentate gyrus cell proliferation and hippocampal BDNF protein levels as well as hippocampal-dependant spatial reference memory using the water plus maze and immobility time on the forced swim test. Both BP and UBP ECS induced very similar types of motor seizures. However, BP ECS but not UBP ECS treatment led to a significant, near 3-fold, increase in cell proliferation (p = 0.026) and BDNF levels (p = 0.01). In the forced swim test, only BP ECS treated animals had a significantly lower immobility time (p = 0.046). There was a trend for similarly reduced hippocampal-dependent memory function in both BP and UBP groups but overall there was not a significant difference between treatment and control animals when tested 10 days after completing allocated treatment. These findings show that, even though both forms of ECS elicited similar motor seizures, UBP ECS was less efficient than BP ECS in inducing antidepressant-related molecular, cellular and behavioural changes. Description: IN_PRESS

Mental Illness in Irish Prisoners

2012-06-21T15:17:54Z

Title: Mental Illness in Irish Prisoners Author: KENNEDY, HARRY Abstract: This is the first systematic and representative survey of psychiatric morbidity in the Irish Prison population, using standardised research diagnostic methods. Five samples have been compiled, including 7% of all men committed to prison in 2003, 50% of all men in custody on remand, 15% of all sentenced men, 9% of all women committed to prison in 2003 and 90% of all women in prison. A total of 1,396 men and 186 women, 1,582 in all. Samples were closely representative of the total populations from which they were drawn. We also mapped the geographic origins of all those committed to prison over a twelve-month period. We found that drugs and alcohol dependence and harmful use were by far the most common problems, present in between 61% and 79% of prisoners. Typically, prisoners were using multiple intoxicants, including alcohol, benzodiazepines, opiates, cannabis and stimulants. For all mental illnesses combined, rates ranged from 16% of male committals to 27% of sentenced men, while in women committed to prison the rate was 41%, with 60% of sentenced women having a mental illness. For the more severe mental illnesses, rates of psychosis were 3.7% amongst men committed to prison, 7.6% amongst men on remand and 2.6% amongst sentenced men. Women prisoners had psychosis in 5.4%. The rate of psychosis in remand prisoners is much higher than in comparable samples from abroad. Depressive disorder was present in 10% of male prisoners and 20% of female prisoners. Most prisoners with mental illness including psychoses, had co-morbid drugs and alcohol problems. We estimated that 3.7% of male committals, 7.5% of men on remand, 2.6% of sentenced men and 5.4% of female prisoners should be diverted to psychiatric services, while as many as 20% of male committals and 32% of female committals needed to be seen by a psychiatrist. This would require approximately 376 transfers from prison to hospital per annum, and between 122 and 157 extra secure psychiatric beds, in addition to extra mental health in-reach clinics. Drug and alcohol problems are so pervasive that traditional ‘clinic’ models of service are unlikely to provide the best solution for most in prison. A generalised strategy which favours drug-free status and motivates inmates could have a significant impact on drug-subcultures in prisons and nationally. Mapping the geographic origins of prisoners showed that urban districts with high deprivation scores were over-represented, though rural deprived districts did not have the same problem. Dublin accounted for 41% of prison committals, compared to 31% expected for it’s population. Description: PUBLISHED

How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans

2012-06-19T13:40:12Z

Title: How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans Author: FRODL, THOMAS; O'KEANE, VERONICA Abstract: There is evidence that excessive stress exposure of the brain, mediated through the neurotoxic effects of cortisol and possibly neuroinflammation, causes damage to brain structure and function: the glucocorticoid cascade hypothesis. Functional changes of hypothalamic-pituitary-adrenal (HPA) axis as well as alterations in brain structures like the hippocampus have been consistently reported in major depression. However, there has not been a lot of emphasis on bringing findings from studies on early childhood stress, HPA axis functioning and hippocampal imaging together. This is the subject for this systematic review of the literature on how developmental stress, specifically childhood maltreatment, may impact on HPA axis function and hippocampal structure. We will also review the literature on the relationship between HPA axis function and hippocampal volume in healthy, depressed and other disease states. There is evidence that prenatal stress and childhood maltreatment is associated with an abnormally developing HPA system, as well as hippocampal volume reduction. Smaller hippocampal volumes are associated with increased cortisol secretion during the day. We conclude that a model integrating childhood maltreatment, cortisol abnormalities and hippocampal volume may need to take other factors into account, such as temperament, genetics or the presence of depression; to provide a cohesive explanation of all the findings. Finally, we have to conclude that the cascade hypothesis, mainly based on preclinical studies, has not been translated enough into humans. While there is evidence that early life maltreatment results in structural hippocampal changes and these are in turn more prominent in subjects with higher continuous cortisol secretion it is less clear which role early life maltreatment plays in HPA axis alteration. Description: IN_PRESS

Neural correlates of treatment outcome in major depression.

2012-04-02T10:06:44Z

Title: Neural correlates of treatment outcome in major depression. Author: FRODL, THOMAS; LISIECKA, DANUTA Abstract: There is a need to identify clinically useful biomarkers in major depressive disorder (MDD). In this context the functional connectivity of the orbitofrontal cortex (OFC) to other areas of the affect regulation circuit is of interest. The aim of this study was to identify neural changes during antidepressant treatment and correlates associated with the treatment outcome. In an exploratory analysis it was investigated whether functional connectivity measures moderated a response to mirtazapine and venlafaxine. Twenty-three drug-free patients with MDD were recruited from the Department of Psychiatry and Psychotherapy of the Ludwig-Maximilians University in Munich. The patients were subjected to a 4-wk randomized clinical trial with two common antidepressants, venlafaxine or mirtazapine. Functional connectivity of the OFC, derived from functional magnetic resonance imaging with an emotional face-matching task, was measured before and after the trial. Higher OFC connectivity with the left motor areas and the OFC regions prior to the trial characterized responders (p<0.05, false discovery rate). The treatment non-responders were characterized by higher OFC-cerebellum connectivity. The strength of response was positively correlated with functional coupling between left OFC and the caudate nuclei and thalami. Differences in longitudinal changes were detected between venlafaxine and mirtazapine treatment in the motor areas, cerebellum, cingulate gyrus and angular gyrus. These results indicate that OFC functional connectivity might be useful as a marker for therapy response to mirtazapine and venlafaxine and to reconstruct the differences in their mechanism of action. Description: PUBLISHED

Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease.

2012-03-05T16:42:35Z

Title: Functional magnetic resonance imaging as a dynamic candidate biomarker for Alzheimer's disease. Author: BOKDE, ARUN LAWRENCE WARREN; HAMPEL, HARALD Abstract: During the last two decades, imaging of neural activation has become an invaluable tool for assessing the functional organization of the human brain in vivo. Due to its widespread application in neuroscience, functional neuroimaging has raised the interest of clinical researchers in its possible use as a diagnostic biomarker. A hallmark feature of many neurodegenerative diseases is their chronic non-linear dynamic and highly complex preclinical course. Neurodegenerative diseases unfold over years to decades through clinically silent and asymptomatic stages of early adaptive, compensatory to pathophysiological (i.e. actively neurodegenerative) and decompensatory mechanisms in the brain – phases that are increasingly being considered as critical for primary and secondary preventive and therapeutic measures. Emerging evidence supports the concept of a potentially fully reversible functional phase that may precede the onset of micro- and macrostructural and cognitive decline, a potentially late-stage “neurodegenerative” phase of a primary neurodegenerative disorder. Alzheimer's disease serves as an ideal model to test this hypothesis supported by the neural network model of the healthy and diseased brain. Being highly dynamic in nature, brain activation and neuronal network functional connectivity represent not only candidate diagnostic but also candidate surrogate markers for interventional trials. Potential caveats of functional imaging are critically reviewed with focus on confound variables such as altered neurovascular coupling as well as parameters related to task- and study design. Description: PUBLISHED

The NOS1 variant rs6490121 is associated with variation in prefrontal function and gray matter density in healthy individuals

2012-02-29T15:27:59Z

Title: The NOS1 variant rs6490121 is associated with variation in prefrontal function and gray matter density in healthy individuals Author: FRODL, THOMAS; DONOHOE, GARY (JAMES); GILL, MICHAEL; CORVIN, AIDEN PETER; NEWELL, FIONA; ROSE, EMMA; FAHEY, CIARA; GARAVAN, HUGH PATRICK; BOKDE, ARUN LAWRENCE WARREN; O'DOHERTY, JOHN PHILIP; MC GRATH, JANE; KELLY, SINEAD; ROBERTSON, IAN H; MORRIS, DEREK Abstract: A common polymorphism within the nitric oxide sythanse-1 (NOS1) gene (rs6490121), initially identified as risk variant for schizophrenia, has been associated with variation in working memory and IQ. Here we investigated how this variation might be mediated at the level of brain structure and function. In healthy individuals (N = 157), voxel based morphometry was used to compare gray matter (GM) volume between homozygous and heterozygous carriers of the ‘G’ allele (i.e. the allele associated with impaired cognition and schizophrenia risk) and homozygous carriers of the non-risk ‘A’ allele. Functional brain imaging data were also acquired from 48 participants during performance of a spatial working memory (SWM) task, and analysed to determine any effect of NOS1 risk status. An a priori region-of-interest analysis identified a significant reduction in ventromedial prefrontal GM volume in ‘G’ allele carriers. Risk carriers also exhibited altered patterns of activation in the prefrontal cortex, caudate, and superior parietal lobe, which were characteristic of abnormal increases in activation in frontoparietal working memory networks and a failure to disengage regions of the default mode network. These functional changes suggest a NOS1-mediated processing inefficiency that may contribute to cognitive dysfunction in schizophrenia. While the mechanisms by which NOS1 may influence brain structure and/or function have not yet been well delineated, these data provide further evidence for a role of NOS1 in risk for schizophrenia via an impact upon cognitive function. Description: PUBLISHED

An X11[alpha]/FSBP complex represses transcription of the GSK3[beta] gene promoter.

2012-01-24T16:08:58Z

Title: An X11[alpha]/FSBP complex represses transcription of the GSK3[beta] gene promoter. Author: MC LOUGHLIN, DECLAN Abstract: X11α is a neuronal adaptor protein that interacts with the amyloid precursor protein (APP) via a centrally located phosphotyrosine binding (PTB) domain to inhibit production of Aβ peptide that is deposited in Alzheimer's disease brains. X11α also contains two C-terminal postsynaptic density-95, discs large, zona occludens 1 (PDZ) domains and we show here that via its PDZ domains, X11α interacts with a novel transcription factor, fibrinogen silencer binding protein (FSBP). Moreover, we demonstrate that an X11α/FSBP complex signals to the nucleus to repress glycogen synthase kinase-3β (GSK3β) promoter activity. GSK3β is a favoured candidate kinase for phosphorylating tau in Alzheimer's disease. Our findings reveal a new function for X11α that may impact on Alzheimer's disease pathogenesis. Description: PUBLISHED