Fleur M. Howells

The effects of mindfulness-based cognitive therapy in patients with bipolar disorder: A controlled functional MRI investigation

BACKGROUND Preliminary research findings have shown that mindfulness-based cognitive therapy improves anxiety and depressive symptoms in bipolar disorder. In this study, we further investigated the effects of MBCT in bipolar disorder, in a controlled fMRI study. METHOD Twenty three patients with bipolar disorder underwent neuropsychological testing and functional MRI. Sixteen of these patients were tested before and after an eight-week MBCT intervention, and seven were wait listed for training and tested at the same intervals. The results were compared with 10 healthy controls. RESULTS Prior to MBCT, bipolar patients reported significantly higher levels of anxiety and symptoms of stress, scored significantly lower on a test of working memory, and showed significant BOLD signal decrease in the medial PFC during a mindfulness task, compared to healthy controls. Following MBCT, there were significant improvements in the bipolar treatment group, in measures of mindfulness, anxiety and emotion regulation, and in tests of working memory, spatial memory and verbal fluency compared to the bipolar wait list group. BOLD signal increases were noted in the medial PFC and posterior parietal lobe, in a repeat mindfulness task. A region of interest analysis revealed strong correlation between signal changes in medial PFC and increases in mindfulness. LIMITATIONS The small control group is a limitation in the study. CONCLUSION These data suggest that MBCT improves mindfulness and emotion regulation and reduces anxiety in bipolar disorder, corresponding to increased activations in the medial PFC, a region associated with cognitive flexibility and previously proposed as a key area of pathophysiology in the disorder.

Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson's disease.

Parkinsons disease (PD) is a progressive neurodegenerative disease of nigrostriatal dopamine (DA) neurons that project from the substantia nigra pars compacta (SNc) to the striatum. To further understand PD, researchers have developed standardized animal models of PD. In this study, Long Evans (LE) rats were unilaterally lesioned by injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle (MFB) of the left hemisphere. The rats were divided into three groups randomly; group 1 (runners) were housed in individual cages with attached running wheels, group 2 (stressed-runners) had access to individual free running wheels, except post-lesion when the rats were subjected to immobilization of the running wheel for 1 h per day for 14 days, as well as one session of 24-h food deprivation and a 7-h shift in the light/dark cycle. Group 3 (non-runnners) were housed individually in cages with attached running wheels that were permanently immobilized. Subcutaneous injection of the DA agonist, apomorphine, caused stressed-runners and non-runners to rotate vigorously away from the side of the lesion (contralaterally). Apomorphine-induced rotations provide a behavioural measure of the extent of the lesion, a depletion of more than 80% of DA neurons is required to produce vigorous contralateral rotations in response to apomorphine injection. Runners rotated significantly less than non-runners and stressed-runners. The number of rotations performed by stressed-runners was not significantly different from non-runners, suggesting that stress had cancelled the neuroprotective effect of running. Immunohistochemical staining for tyrosine hydroxylase in the SNc revealed slightly less destruction of DA neurons in the runners than in stressed-runners or non-runners, although these differences did not achieve statistical significance. The behavioural results confirm a previous finding suggesting that voluntary exercise is neuroprotective. A novel finding is that mild stressors cancel the neuroprotection afforded by voluntary exercise.

Perceived mental effort correlates with changes in tonic arousal during attentional tasks

BackgroundIt has been suggested that perceived mental effort reflects changes in arousal during tasks of attention. Such changes in arousal may be tonic or phasic, and may be mediated by the locus-coeruleus norepinephrine (LC-NE) system. We hypothesized that perceived mental effort during attentional tasks would correlate with tonic changes in cortical arousal, as assessed by relative electroencephalogram (EEG) band power and theta/beta ratio, and not with phasic changes in cortical arousal, assessed by P300 amplitude and latency.MethodsForty-six healthy individuals completed tasks that engage the anterior and posterior attention networks (continuous performance task, go/no-go task, and cued target detection task). During completion of the three attentional tasks a continuous record of tonic and phasic arousal was taken. Cortical measures of arousal included frequency band power, theta/beta ratios over frontal and parietal cortices, and P300 amplitude and latency over parietal cortices. Peripheral measures of arousal included skin conductance responses, heart rate and heart rate variance. Participants reported their perceived mental effort during each of the three attentional tasks.ResultsFirst, changes in arousal were seen from rest to completion of the three attentional tasks and between the attentional tasks. Changes seen between the attentional tasks being related to the task design and the attentional network activated. Second, perceived mental effort increased when demands of the task increased and correlated with left parietal beta band power during the three tasks of attention. Third, increased mental effort during the go/no-go task and the cued target detection task was inversely related to theta/beta ratios.ConclusionThese results indicate that perceived mental effort reflects tonic rather than phasic changes in arousal during tasks of attention. We suggest that perceived mental effort may reflect in part tonic activity of the LC-NE system in healthy individuals.

Mindfulness based cognitive therapy improves frontal control in bipolar disorder: a pilot EEG study

BackgroundCognitive processing in Bipolar Disorder is characterized by a number of attentional abnormalities. Mindfulness Based Cognitive Therapy combines mindfulness meditation, a form of attentional training, along with aspects of cognitive therapy, and may improve attentional dysfunction in bipolar disorder patients.Methods12 euthymic BD patients and 9 control participants underwent record of electroencephalography (EEG, band frequency analysis) during resting states (eyes open, eyes closed) and during the completion of a continuous performance task (A-X version, EEG event-related potential (ERP) wave component analysis). The individuals with BD completed an 8-week MBCT intervention and record of EEG was repeated.Results(1) Brain activity, individuals with BD showed significantly decreased theta band power, increased beta band power, and decreased theta/beta ratios during the resting state, eyes closed, for frontal and cingulate cortices. Post MBCT intervention improvement over the right frontal cortex was seen in the individuals with BD, as beta band power decreased. (2) Brain activation, individuals with BD showed a significant P300-like wave form over the frontal cortex during the cue. Post MBCT intervention the P300-like waveform was significantly attenuated over the frontal cortex.ConclusionsIndividuals with BD show decreased attentional readiness and activation of non-relevant information processing during attentional processes. These data are the first that show, MBCT in BD improved attentional readiness, and attenuated activation of non-relevant information processing during attentional processes.

The neurobiology of methamphetamine induced psychosis

Chronic methamphetamine abuse commonly leads to psychosis, with positive and cognitive symptoms that are similar to those of schizophrenia. Methamphetamine induced psychosis (MAP) can persist and diagnoses of MAP often change to a diagnosis of schizophrenia over time. Studies in schizophrenia have found much evidence of cortical GABAergic dysfunction. Methamphetamine psychosis is a well studied model for schizophrenia, however there is little research on the effects of methamphetamine on cortical GABAergic function in the model, and the neurobiology of MAP is unknown. This paper reviews the effects of methamphetamine on dopaminergic pathways, with focus on its ability to increase glutamate release in the cortex. Excess cortical glutamate would likely damage GABAergic interneurons, and evidence of this disturbance as a result of methamphetamine treatment will be discussed. We propose that cortical GABAergic interneurons are particularly vulnerable to glutamate overflow as a result of subcellular location of NMDA receptors on interneurons in the cortex. Damage to cortical GABAergic function would lead to dysregulation of cortical signals, resulting in psychosis, and further support MAP as a model for schizophrenia.

Neuroimaging effects of prenatal alcohol exposure on the developing human brain: a magnetic resonance imaging review

Objective This paper reviews the magnetic resonance imaging (MRI) literature on the effects of prenatal alcohol exposure on the developing human brain. Method A literature search was conducted through the following databases: PubMed, PsycINFO and Google Scholar. Combinations of the following search terms and keywords were used to identify relevant studies: ‘alcohol’, ‘fetal alcohol spectrum disorders’, ‘fetal alcohol syndrome’, ‘FAS’, ‘FASD’, ‘MRI’, ‘DTI’, ‘MRS’, ‘neuroimaging’, ‘children’ and ‘infants’. Results A total of 64 relevant articles were identified across all modalities. Overall, studies reported smaller total brain volume as well as smaller volume of both the white and grey matter in specific cortical regions. The most consistently reported structural MRI findings were alterations in the shape and volume of the corpus callosum, as well as smaller volume in the basal ganglia and hippocampi. The most consistent finding from diffusion tensor imaging studies was lower fractional anisotropy in the corpus callosum. Proton magnetic resonance spectroscopy studies are few to date, but showed altered neurometabolic profiles in the frontal and parietal cortex, thalamus and dentate nuclei. Resting-state functional MRI studies reported reduced functional connectivity between cortical and deep grey matter structures. Discussion There is a critical gap in the literature of MRI studies in alcohol-exposed children under 5 years of age across all MRI modalities. The dynamic nature of brain maturation and appreciation of the effects of alcohol exposure on the developing trajectory of the structural and functional network argue for the prioritisation of studies that include a longitudinal approach to understanding this spectrum of effects and potential therapeutic time points.

Effects of early life trauma are dependent on genetic predisposition: a rat study

BackgroundTrauma experienced early in life increases the risk of developing a number of psychological and/or behavioural disorders. It is unclear, however, how genetic predisposition to a behavioural disorder, such as attention-deficit/hyperactivity disorder (ADHD), modifies the long-term effects of early life trauma. There is substantial evidence from family and twin studies for susceptibility to ADHD being inherited, implying a strong genetic component to the disorder. In the present study we used an inbred animal model of ADHD, the spontaneously hypertensive rat (SHR), to investigate the long-term consequences of early life trauma on emotional behaviour in individuals predisposed to developing ADHD-like behaviour.MethodsWe applied a rodent model of early life trauma, maternal separation, to SHR and Wistar-Kyoto rats (WKY), the normotensive control strain from which SHR were originally derived. The effects of maternal separation (removal of pups from dam for 3 h/day during the first 2 weeks of life) on anxiety-like behaviour (elevated-plus maze) and depressive-like behaviour (forced swim test) were assessed in prepubescent rats (postnatal day 28 and 31). Basal levels of plasma corticosterone were measured using radioimmunoassay.ResultsThe effect of maternal separation on SHR and WKY differed in a number of behavioural measures. Similar to its reported effect in other rat strains, maternal separation increased the anxiety-like behaviour of WKY (decreased open arm entries) but not SHR. Maternal separation increased the activity of SHR in the novel environment of the elevated plus-maze, while it decreased that of WKY. Overall, SHR showed a more active response in the elevated plus-maze and forced swim test than WKY, regardless of treatment, and were also found to have higher basal plasma corticosterone compared to WKY. Maternal separation increased basal levels of plasma corticosterone in SHR females only, possibly through adaptive mechanisms involved in maintaining their active response in behavioural tests. Basal plasma corticosterone was found to correlate positively with an active response to a novel environment and inescapable stress across all rats.ConclusionSHR are resilient to the anxiogenic effects of maternal separation, and develop a non-anxious, active response to a novel environment following chronic mild stress during the early stages of development. Our findings highlight the importance of genetic predisposition in determining the outcome of early life adversity. SHR may provide a model of early life trauma leading to the development of hyperactivity rather than anxiety and depression. Basal levels of corticosterone correlate with the behavioural response to early life trauma, and may therefore provide a useful marker for susceptibility to a certain behavioural temperament.

Glutamate-stimulated release of norepinephrine in hippocampal slices of animal models of attention-deficit/hyperactivity disorder (spontaneously hypertensive rat) and depression/anxiety-like behaviours (Wistar-Kyoto rat).

Norepinephrine is known to play an integral role in different aspects of behaviour, such as attention and arousal. It has also been implicated in the neurobiology of attention-deficit/hyperactivity disorder (ADHD). The present study was undertaken to determine the differential effects of glutamate on norepinephrine release in hippocampal slices of several rat strains. Two of the strains used in this study model behavioural disorders i.e. spontaneously hypertensive rats (SHR) mimic the behavioural characteristics of ADHD and Wistar-Kyoto (WKY) rats have been used to model depression/anxiety-like behaviours. To achieve the aims of this study, an in vitro superfusion technique was used to determine glutamate-stimulated release of radioactively labelled norepinephrine in hippocampal slices. The results show (1) SHR and Wistar rats released significantly more [(3)H]norepinephrine in response to a 1-min pulse of glutamate (1 mM) than WKY, Sprague-Dawley and Long-Evans rats. (2) Glutamate-stimulated release of [(3)H]norepinephrine was reduced by the AMPA receptor antagonist, CNQX (1 muM), suggesting that AMPA receptors are involved. (3) Exposure of hippocampal slices to a second and third 1-min pulse of glutamate revealed significant decreases in the peaks of [(3)H]norepinephrine release suggesting internalization of AMPA receptors. The rate of AMPA receptor internalization was slower in SHR than in WKY. (4) The NMDA receptor antagonist, MK-801 (10 microM) increased glutamate-stimulated release of [(3)H]norepinephrine in SHR hippocampus. This effect was blocked by CNQX, suggesting that AMPA receptors were required for the NMDA effect and that there was an NMDA component of AMPA receptor internalization in SHR hippocampus which was not evident in WKY. The present findings reveal a novel NMDA component that influences AMPA receptor-mediated regulation of norepinephrine release in SHR hippocampus.

1H-magnetic resonance spectroscopy (1H-MRS) in methamphetamine dependence and methamphetamine induced psychosis

BACKGROUND Methamphetamine (MA) use has been shown to decrease n-acetyl-aspartate (NAA), a marker of neuronal integrity and viability, on (1)H magnetic resonance spectroscopy ((1)H-MRS). However, little work has compared (1)H-MRS in MA dependent individuals and MA dependent individuals with MA induced psychotic disorder (MAP). METHODS Twenty six participants with MA dependence (sixteen without psychosis, ten with psychosis - MAP) and nineteen healthy controls underwent 2D-chemical shift imaging (1)H-MRS, which included voxels in the anterior cingulate cortices (ACC), dorsolateral prefrontal cortices (DLPFC), and frontal white matter. We compared metabolite concentrations relative to phosphocreatine+creatine (PCr+Cr) for n-acetyl-aspartate (NAA), n-acetyl-aspartate+n-acetyl-aspartyl-glutamate (NAA+NAAG), glutamate (Glu), glutamate+glutamine (Glu+Gln), myo-inositol, and glycerophosphocholine+phosphocholine (GPC+PCh) across groups. RESULTS The MA groups showed significantly decreased relative NAA metabolite concentrations for right ACC and right DLPFC, compared with control group. The MA dependent group only showed significantly decreased choline metabolites for right DLPFC, compared with control group. The MAP groups relative NAA metabolite concentrations were significantly correlated with age of initial use and duration of MA use, these correlates were not apparent in MA dependent group. CONCLUSION MA use is associated with decreased neuronal integrity and viability, specifically in the right ACC and right DLPFC. MA dependence showed active neurodegeneration in the right DLPFC, this was not apparent in the MAP group and may be related to the use of antipsychotic medication in the MAP group. The effects of MA use in MAP suggest that age of initial use presents a mismatch of neuronal plasticity, in frontal white vs. gray matter and duration of use relates to decreased neuronal integrity and viability. Further study is warranted from this initial study of (1)H-MRS in MAP, in particular longitudinal assessment of these individuals both neurobiologically ((1)H-MRS) and clinically - to determine disease progression.

Electrophysiological indices of visual food cue-reactivity. Differences in obese, overweight and normal weight women

Heightened food cue-reactivity in overweight and obese individuals has been related to aberrant functioning of neural circuitry implicated in motivational behaviours and reward-seeking. Here we explore the neurophysiology of visual food cue-reactivity in overweight and obese women, as compared with normal weight women, by assessing differences in cortical arousal and attentional processing elicited by food and neutral image inserts in a Stroop task with record of EEG spectral band power and ERP responses. Results show excess right frontal (F8) and left central (C3) relative beta band activity in overweight women during food task performance (indicative of pronounced early visual cue-reactivity) and blunted prefrontal (Fp1 and Fp2) theta band activity in obese women during office task performance (suggestive of executive dysfunction). Moreover, as compared to normal weight women, food images elicited greater right parietal (P4) ERP P200 amplitude in overweight women (denoting pronounced early attentional processing) and shorter right parietal (P4) ERP P300 latency in obese women (signifying enhanced and efficient maintained attentional processing). Differential measures of cortical arousal and attentional processing showed significant correlations with self-reported eating behaviour and body shape dissatisfaction, as well as with objectively assessed percent fat mass. The findings of the present study suggest that heightened food cue-reactivity can be neurophysiologically measured, that different neural circuits are implicated in the pathogenesis of overweight and obesity, and that EEG techniques may serve useful in the identification of endophenotypic markers associated with an increased risk of externally mediated food consumption.