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Metabolic dysregulation is currently considered a major risk factor for hippocampal pathology. The aim of the present study was to characterize the influence of key metabolic drivers on functional connectivity of the hippocampus in healthy adults.
Insulin resistance was directly quantified by measuring steady-state plasma glucose (SSPG) concentration during the insulin suppression test and fasting levels of insulin, glucose, leptin, and cortisol, and measurements of body mass index and waist circumference were obtained in a sample of healthy cognitively intact adults (n = 104). Resting-state neuroimaging data were also acquired for the quantification of hippocampal functional cohesiveness and integration with the major resting-state networks (RSNs). Data-driven analysis using unsupervised machine learning (k-means clustering) was then employed to identify clusters of individuals based on their metabolic and functional connectivity profiles.
K-means clustering identified two clusters of increasing metabolic deviance evidenced by cluster differences in the plasma levels of leptin (40.36 (29.97) vs. 27.59 (25.58) μg/L) and the degree of insulin resistance (SSPG concentration: 161.63 (65.27) vs. 125.72 (66.81) mg/dL). Individuals in the cluster with higher metabolic deviance showed lower functional cohesiveness within each hippocampus and lower integration of posterior and anterior components of the left and right hippocampus with the major RSNs. The two clusters did not differ in general intellectual ability or episodic memory.
We identified two clusters of individuals differentiated by abnormalities in insulin resistance, leptin levels, and hippocampal connectivity, with one of the clusters showing greater deviance. These findings support the link between metabolic dysregulation and hippocampal function even in nonclinical samples.
The Adolescent Brain and Cognitive Development (ABCD) study, a US population-based sample of 10 year-olds, offers a unique opportunity to examine the neural correlates of manic-like symptoms presenting in children about to enter adolescence.
The study will avail of the rich dataset of over 11,000 children aged 9-10 years at enrolment using data from the baseline and 2-year follow-up assessment. The analyses aim to track the evolution of manic-like symptoms between the two follow-up waves and test their sensitivity of their association with brain correlates.
Data analyses are ongoing and will focus on changes in manic-like symptoms, focusing on youth with remitting, persistent and emerging symptoms and examine their associations with brain structure and resting-state functional connectivity.
The results will inform about the early trajectory of manic-like symptoms and offer new insights into their brain-related correlates.
Childhood exposure to social risk has the potential to disrupt brain development and increase vulnerability to adverse mental health outcomes. Here, we examine the effect of adversity on brain structure and psychopathology in the Adolescent Brain and Cognitive Development (ABCD) study, a US population-based sample of 10 year-olds.
Personal, caregiver, family and neighborhood characteristics were considered in 9299 unrelated children [age: mean (sd)=9.9 y (0.6); 53% males]. Hidden Markov Models were used identify clusters of participants based on their psychosocial exposure. The identified clusters were compared in terms of current psychopathology, lifetime psychiatric diagnosis, intelligence and brain structure.
ABCD participants clustered in to a “disadvantaged” group (N=4205) with multiple adverse exposures, and an “enriched” group (N= 5094) with limited exposure to adversity and multiple protective factors. Compared to the enriched group, the disadvantaged group had higher levels of all types of psychopathology and lifetime psychiatric diagnoses; lower scores on fluid and crystallized intelligence; smaller subcortical volumes; thinner sensorimotor cortices and thicker cortex in frontal regions; smaller surface area in temporal regions and larger surface area in the posterior cingulate cortices (all p<0.05 following Bonferroni correction for multiple testing).
Social adversity has significant and wide-ranging consequences for brain development and psychopathology, that shows little specificity for types of symptoms.
The pandemic caused by coronavirus disease 2019 (COVID-19) has forced governments to implement strict social mitigation strategies to reduce the morbidity and mortality from acute infections. These strategies, however, carry a significant risk for mental health, which can lead to increased short-term and long-term mortality and is currently not included in modeling the impact of the pandemic.
We used years of life lost (YLL) as the main outcome measure, applied to Switzerland as an example. We focused on suicide, depression, alcohol use disorder, childhood trauma due to domestic violence, changes in marital status, and social isolation, as these are known to increase YLL in the context of imposed restriction in social contact and freedom of movement. We stipulated a minimum duration of mitigation of 3 months based on current public health plans.
The study projects that the average person would suffer 0.205 YLL due to psychosocial consequence of COVID-19 mitigation measures. However, this loss would be entirely borne by 2.1% of the population, who will suffer an average of 9.79 YLL.
The results presented here are likely to underestimate the true impact of the mitigation strategies on YLL. However, they highlight the need for public health models to expand their scope in order to provide better estimates of the risks and benefits of mitigation.
A single nucleotide polymorphism within the CACNA1C gene (rs1006737) has been found to confer increased risk of Bipolar Disorder (BD) and has been linked to altered neuronal gating and emotional behaviour. As current models of BD suggest abnormal integration within frontolimbic networks, our aim was to explore the effect of the CACNA1C genotype on prefrontal and limbic activation.
We genotyped 90 participants from the Vulnerability to Bipolar Disorder Study comprising of 41 euthymic BD patients and 49 healthy controls. Functional magnetic resonance imaging data were obtained while participants performed a fearful versus neutral facial affect processing task.
We found a significant diagnosis by genotype interaction with BD patients homozygous for the risk allele having reduced prefrontal activation compared to the other groups.
The present findings support the hypothesis that the rs1006737 polymorphism in the CACNA1C gene confers increased risk of BD by modulating amygdala and PFC activation during emotional processing.
There is significant overlap between the cortical network involved in fearful face perception and regional abnormalities identified in patients with bipolar disorder. The primary aim of this study was to measure effective connectivity arising from Dynamic Causal Modelling (DCM) to identify differences within this network in a group of patients with bipolar disorder and controls during an affective processing task.
Functional MRI was used to record brain activations from 52 euthymic patients with bipolar disorder and 44 healthy controls engaged in a fearful versus neutral facial affect recognition task. We used Bayesian model selection to identify the best model of effective connectivity, as well as a random-effects analysis. Additionally, the endogenous connections and modulatory influences were extracted and further analyzed.
Within the network subserving fearful facial affect recognition, patients with bipolar disorder demonstrated reduced connectivity from the inferior occipital gyrus to the fusiform gyrus compared to healthy controls. Furthermore this connection when modulated by fear showed a reduction in strength in patients with bipolar disorder.
Bipolar disorder was associated with deficits early in the processing of facial affect suggesting the possibility of perceptual abnormalities being associated with the disorder.
Dr Frangou was supported by a NARSAD Independent Investigator Award
Working memory (WM) deficits are among the core cognitive abnormalities in schizophrenia. WM is subserved by widely distributed fronto-parietal networks and is undergoing robust development during adolescence. Studying the neural correlates of WM dysfunction in early-onset schizophrenia (EOS) will advance our understanding of aberrant neurodevelopmental processes in the disorder.
Nineteen patients with EOS aged 13-19 and 20 matched healthy participants underwent functional Magnetic Resonance Imaging (fMRI) as they performed a N-back verbal WM task with 3 levels of difficulty (1-back, 2-back, 3-back). Following matching for task performance, 14 patients were compared to 20 controls, using non-parametric whole brain and region of interest approaches followed by psycho-physiological interaction analysis (PPI) with seed voxel from the left parietal cluster.
Regions within the left prefrontal cortex, the left insula and bilateral anterior cingulate cortex showed reduced activation in EOS patients compared to healthy participants at the 2-back condition. In addition, ROI analysis at the same condition revealed hypoactivation in the EOS group with large effect sizes for left prefrontal and parietal regions. The PPI results revealed negative functional connectivity in the healthy participants’ group but not in EOS between left parietal and right parietal and bilateral frontal regions.
Our results support compromised function within the left prefrontal-cingulate network and left insula during the N-Back verbal WM task in patients with EOS compared to healthy participants. They also indicate the possibility of more widespread fronto-parietal network dysfunction, most noted in the left hemisphere in the disorder.
We wished to examine whether patterns of neural engagement during emotional processing could distinguish patients with Bipolar Disorder (BD) from their relatives with Major Depressive Disorder (MDD) and their psychiatrically healthy relatives.
Functional magnetic resonance imaging (fMRI) data were collected during a sad facial affect recognition task from 41 remitted BD patients, 40 of their first degree relatives (15 of whom had MDD) and 51 healthy controls. Data were analysed in SPM5.
A) Compared to controls, all individuals with genetic predisposition to BD showed increased activation in temporal lobe regions.
B) Compared to BD patients, MDD relatives had reduced activation in the left posterior cingulate (BA31) and the orbitofrontal cortex (BA11)
C) Compared to their healthy relatives, BD patients showed increased activation in somatosensory cortices bilaterally (BA3 and BA5) and in the posterior cingulate gyrus (BA30) on the left and reduced activation in the right cerebellum and the right inferior frontal gyrus (BA47).
D) Compared to their healthy relatives, MDD relatives showed reduced activation in the left superior frontal gyrus (BA10).
Our results suggest that:
(a) genetic predisposition to BD was associated with increased activation in distal nodes of the ventral visual pathway within the temporal lobe
(b) disease expression for mood disorders was associated with reduced neural responses in the PFC
(c) resilience in healthy relatives was associated with enhanced PFC engagement
(d) loci identified showed partial specificity for different clinical phenotypes indicative of partially segregated processes underpinning disease and resilience for mood disorders.
In Early Onset Schizophrenia (EOS; onset before the 18th birthday) late brain maturational changes may interact with disease mechanisms leading to a wave of back to front structural changes during adolescence. To further explore this effect we examined the relationship between age of onset and duration of illness on brain morphology in adolescents with EOS.
Subjects and methods
Structural brain magnetic resonance imaging scans were obtained from 40 adolescents with EOS. We used Voxel Based Morphometry and multiple regressions analyses, implemented in SPM, to examine the relationship between gray matter volume with age of onset and illness duration.
Age of onset showed a positive correlation with regional gray matter volume in the right superior parietal lobule (Brodmann Area 7). Duration of illness was inversely related to regional gray matter volume in the left inferior frontal gyrus (BA 11/47).
Parietal gray matter loss may contribute to the onset of schizophrenia while orbitofrontal gray matter loss is associated with illness duration.
Poor decision-making is a prominent feature of Bipolar Disorder (BD) suggesting that patients may be impaired in affective aspects of complex problem solving. We examined the neural correlates of emotional learning (EL) in remitted BD patients and healthy controls (HC).
Subjects comprised three groups: (a) 11 remitted BD patients with EL (b) 11 remitted BD patients who failed to show EL and, (c) 11 HC with EL. All groups were demographically matched. Patients were also matched on clinical variables. Participants underwent functional magnetic resonance imaging (fMRI) while performing the Iowa Gambling Task. In the active condition participants relied upon EL to weigh up short-term rewards against long-term losses, in order to achieve an optimal gambling strategy. The control condition was identical to the gambling condition except for the reward/loss component. Behavioural and neural responses associated with the overall task performance were assessed.
Regardless of their performance in EL, BD patients, compared to HC, showed increased task-related activation in the insula and ventral anterior cingulate gyrus. BD patients with EL showed increased activation in left frontopolar and ventrolateral prefrontal cortices while reduced activation was noted in the same regions in BD patients who failed to show EL.
BD patients showed evidence of increased limbic activation associated with affective decision-making. Their ability to attain emotional learning was associated with increased recruitment of frontopolar and ventral prefrontal cortex regions. This finding may reflect a successful compensatory response to limbic overactivation during affective decision-making.
Neuroimaging is one of the most promissing avenues for exploring psychiatric disorders in general and schizophrenia in particular both in terms of aetiology but also pathophysiology and treatment response.The aim of this workshop is to discuss possible avenues for Europe-wide collaborative research in neuroimaging and the implications it has for training and general infrastructure
The workshop leaders with discuss at their individual presentations the current vision for more uniform approach to neuroimaging across Europe, steps already taken towards it and plans for the future.
The organisers of the workshop hope that a consensus view will emerge to move neuroimaging research in schizophrenia into a Europe wide platform.
The future rests is collaborative large scale multicentre research.
Bipolar Disorder (BD) is associated with structural and functional abnormalities in prefrontal and limbic areas implicated in emotional processing. Lamotrigine (LTG) has been shown to improve depressive features in BD although its mechanism of therapeutic action is not known. The current study examined the possibility that LTG may improve functional activation within the neural circuitry involved in emotional processing.
We used functional Magnetic Resonance Imaging to examine changes in patterns of brain activation in 12 stable BD patients (a) compared to healthy controls when medication free and (b) after 12 weeks of Lamotrigine monotherapy whilst performing a sad facial affect recognition task on both occasions.
At baseline, compared to controls, BD patients showed overactivity in response to sad facial affect recognition in temporal lobe regions and under-activity in dorsal medial and right ventrolateral PFC and the dorsal cingulate gyrus. After 4 weeks of LTG monotherapy, patients showed reduced activation in temporal regions and increased neural response in dorsomedial and ventrolateral prefrontal regions.
This preliminary evidence suggests the possibility that LTG may enhance functional activation within prefrontal regions responsible for emotional self-regulation.
Declaration of interest
This study was supported by an unrestricted grant from GlaxoSmithKline
Selective serotonin reuptake inhibitors (SSRIs) are thought to exert their therapeutic action through increased serotonergic neurotransmission and hippocampal neurogenesis. Both of these processes may also contribute to the disinhibiting effects of SSRIs currently considered to contribute to potential risk of suicide or self-harm.
This study examined the acute (3 hours) and chronic (28 days) effects of citalopram administration on response inhibition and contextual processing (a hippocampal related function). Twenty healthy male volunteers were randomised to either placebo or 20 mg of oral citalopram for 28 days in a double blind design. Response inhibition was measured with the degraded symbol continuous performance test (DS-CPT) and contextual processing with a visual delayed non-matched to sample task (DNMS).
Citalopram treatment did not produce measurable changes to reaction time, hit rate and false alarms in the DS-CPT at any time point. The citalopram treated group underperformed in the DNMTS after acute treatment and this decrement appeared to persist at 28 days.
Our results suggest that SSRI treatment may lead to small but measurable decrements in contextual processing, which require further confirmation, and evaluation in clinical populations.
Emotional regulation plays a pivotal role in socialization and personal development. However, little is known about the time course of emotional responses and the interaction with the subjective assessment of emotional intensity. The aim of this project was to examine the time course of emotional responses to visual stimuli when they naturally subside and when they are cognitively suppressed.
Healthy volunteers (n=48) viewed 54 images, each lasting for 6 sec, taken from the International Affective Picture System (18 positive, 18 negative, 18 neutral). In the passive condition, subjects had to press a button to view the next image when their response had subsided. In the active condition, subjects had to press a button to view the next image when their response was successfully suppressed. After each presentation, participants rated the intensity of their response on a scale from 1 (lowest) to 9 (highest). Time to resolution (TTR) after image presentation and intensity ratings were averaged (mean±SD).
TTR (seconds) for neutral images was 7.22 ± 7.91 and 4.49 ± 5.41 for passive and active condition, respectively. For positive images, 12.1± 9.2 and 8.66 ± 7.13 for passive and active condition, respectively. For negative images, 15.68 ±10.14 and 11.42 ±8.25 for passive and active condition, respectively. TTR was statistically significantly shorter (p<0.006) for all images during suppression. TTR in both conditions correlated positively with intensity of emotional response.
TTR of emotional responses to emotionally valenced images increases with intensity of the associated response and decreases with voluntary suppression.
Bipolar Disorder (BD) is associated with impairment in emotional self-regulation and verbal working memory. Lamotrigine (LTG) is effective in the clinical management of BD.
To investigate whether treatment with LTG is coupled with altered function within neural circuits subserving emotional processing and verbal working memory, in a BDI sample.
Functional Magnetic Resonance Imaging (MRI) was used to explore blood oxygenation level-dependent (BOLD) response across the whole brain in 12 stable BDI patients at baseline and following 12 weeks of LGT monotherapy. Stimuli were presented in a block-design while individuals performed a verbal working memory (N-back sequential letter) task and in an event-related fashion during an angry facial affect recognition task. Data was acquired using a 1.5-Tesla MRI scanner and analysed using SPM2. Group activation maps were generated for each task and for the drug-free and post-medication condition. A threshold of p < 0.001 was used. Effect of LGT on brain activation during tasks was explored using a random-effects, within-group comparison.
In both tasks, LGT monotherapy was associated with increased BOLD signal when compared to baseline in a number of brain regions, mostly within the prefrontal cortex and cingulate gyrus. All foci of increased activation with LTG monotherapy were observed within cortical regions normally engaged in verbal working memory and facial affect processing.
LTG monotherapy in BD patients may enhance cortical function within neural circuits involved in memory and emotional self-regulation.
This study was supported by an unrestricted GlaxoSmithKline grant.
The complex sulco-gyral pattern results from fetal and early childhood processes that shape the cortex anatomy from a smooth lissencephalic structure to a highly convoluted surface. Abnormal brain maturation has been suggested as risk factor for schizophrenia. Thus, measures of the cortical folding pattern could provide cues for the neurodevelopmental aspects of pathopsychology.
Brain morphometry softwares providing 3D sulci descriptors (e.g. surface) from MRI (Mangin, 2004 ; Cachia, 2007). This automatized method avoids biases inherent to image normalisation and partial volume effect. Therefore, statistics on sulcal measurements should generalize across patients. T1 MRI datasets were studied in at-risk subjects, adolescent onset schizophrenia, and patients with treatment-resistant depression and auditory hallucinations.
Decreased in sulci surface were detected in whole brain sulcal indices and in regional sulcal indices. Decreases in global sulcal indices were detected in most patient groups, except in at risk subjects. Decreases in local sulcal indices were detected in langage-related areas in resistant hallucinators (Cachia 2007), and confined to left temporal regions in adolescent schizophrenia (Pentilla, submitted). In patients with treatment-resistant depression, sulci descriptors differed in right hemisphere sulci adjacent to limbic regions (Pentilla, submitted).
The potential of the gyrification pattern for the inference of neuroimage-based developmental biomarkers will be further examined using multivariate classification approaches (Duchesnay 2006).
. Mangin et al., Neuroimage 2004 - Cachia et al., Neuroimage 2007 – Duchesnay et al., Neuroimage 2006
To examine genetic influences the anatomy of the Corpus Callosum (CC) in Bipolar Disorder (BD) by examining first-degree relatives in addition to BD patients.
We compared CCl size and shape in 180 individuals: 70 with BD, 45 of their unaffected first-degree relatives, and 75 healthy controls. The CC was extracted from a mid-sagittal slice from T1-weighted magnetic resonance images; its total area, length and curvature were compared across groups. A non-parametric permutation method was used to examine for alterations in width of the callosum along 39 points.
Validating our previous findings, a significant global reduction in CC thickness was seen in BD patients, with a disproportionate thinning in the anterior body. First-degree relatives did not differ in CC size or shape from controls. Duration of illness was associated with thinning in the anterior body, whereas Lithium treatment associated with thicker anterior CC midbody.
Global and regional CC thinning is a disease related feature of BD and may not represent a marker of familial disposition.
Emotional dysregulation in Bipolar Disorder (BD) is thought to be linked with prefrontal cortex (PFC) dysfunction associated with cognitive control coupled with increased or aberrant activation within regions associated with emotional processing.
To determine the common and distinct patterns of functional brain abnormalities during affective and emotionally neutral cognitive processing in BD.
Current models of BD emphasise the relationship between mood dysregulation and fronto-limbic dysfunction during affective or “hot” processing. However, they do not account for deficits in emotionally neutral or “cold” tasks of memory and executive function which are also present in BD. Therefore the purpose of this study was to examine the neural correlates of affective decision making and working memory in BD.
Participants were 36 euthymic BD patients and 37 healthy controls matched for age, gender and IQ. FMRI was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task as respective exemplars of “hot” and “cold” processing.
There were no group differences in performance on either task. BD patients demonstrated a pattern of inefficient engagement within the ventral frontopolar PFC in both the IGT and n-back. These abnormalities showed task-related segregation along the medial-lateral dimension for “hot” and “cold” processing respectively. Patients also showed greater activation in the anterior cingulate cortex during the IGT and in the insula during the n-back. These regions are thought to respond to markers of autonomic arousal.
These data demonstrate ventral frontopolar PFC inefficiency as a shared abnormality underpinning both “hot” and “cold” processing deficits in BD.
Current models for mood disorders and particularly bipolar disorder focus on increaesed activation within the limbic system coupled with reduced inhibitory control from the prefrontal cortex. This presentation will focus on functional magnetic resonance imaging studies that highlight limbic-prefrontal interactions in Mood Disorders and on the potential effect of antidepressants and mood stablisers on these neural networks.