Evaluation of data imputation strategies in complex, deeply-phenotyped data sets: the case of the EU-AIMS Longitudinal European Autism Project.

An increasing number of large-scale multi-modal research initiatives has been conducted in the typically developing population, e.g. Dev. Cogn. Neur. 32:43-54, 2018; PLoS Med. 12(3):e1001779, 2015; Elam and Van Essen, Enc. Comp. Neur., 2013, as well as in psychiatric cohorts, e.g. Trans. Psych. 10(1):100, 2020; Mol. Psych. 19:659-667, 2014; Mol. Aut. 8:24, 2017; Eur. Child and Adol. Psych. 24(3):265-281, 2015. Missing data is a common problem in such datasets due to the difficulty of assessing multiple measures on a large number of participants. The consequences of missing data accumulate when researchers aim to integrate relationships across multiple measures. Here we aim to evaluate different imputation strategies to fill in missing values in clinical data from a large (total N = 764) and deeply phenotyped (i.e. range of clinical and cognitive instruments administered) sample of N = 453 autistic individuals and N = 311 control individuals recruited as part of the EU-AIMS Longitudinal European Autism Project (LEAP) consortium. In particular, we consider a total of 160 clinical measures divided in 15 overlapping subsets of participants. We use two simple but common univariate strategies-mean and median imputation-as well as a Round Robin regression approach involving four independent multivariate regression models including Bayesian Ridge regression, as well as several non-linear models: Decision Trees (Extra Trees., and Nearest Neighbours regression. We evaluate the models using the traditional mean square error towards removed available data, and also consider the Kullback-Leibler divergence between the observed and the imputed distributions. We show that all of the multivariate approaches tested provide a substantial improvement compared to typical univariate approaches. Further, our analyses reveal that across all 15 data-subsets tested, an Extra Trees regression approach provided the best global results. This not only allows the selection of a unique model to impute missing data for the LEAP project and delivers a fixed set of imputed clinical data to be used by researchers working with the LEAP dataset in the future, but provides more general guidelines for data imputation in large scale epidemiological studies.

Comparison of neural substrates of temporal discounting between youth with autism spectrum disorder and with obsessive-compulsive disorder.

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share abnormalities in hot executive functions such as reward-based decision-making, as measured in the temporal discounting task (TD). No studies, however, have directly compared these disorders to investigate common/distinct neural profiles underlying such abnormalities. We wanted to test whether reward-based decision-making is a shared transdiagnostic feature of both disorders with similar neurofunctional substrates or whether it is a shared phenotype with disorder-differential neurofunctional underpinnings. METHODS: Age and IQ-matched boys with ASD (N = 20), with OCD (N = 20) and 20 healthy controls, performed an individually-adjusted functional magnetic resonance imaging (fMRI) TD task. Brain activation and performance were compared between groups. RESULTS: Boys with ASD showed greater choice-impulsivity than OCD and control boys. Whole-brain between-group comparison revealed shared reductions in ASD and OCD relative to control boys for delayed-immediate choices in right ventromedial/lateral orbitofrontal cortex extending into medial/inferior prefrontal cortex, and in cerebellum, posterior cingulate and precuneus. For immediate-delayed choices, patients relative to controls showed reduced activation in anterior cingulate/ventromedial prefrontal cortex reaching into left caudate, which, at a trend level, was more decreased in ASD than OCD patients, and in bilateral temporal and inferior parietal regions. CONCLUSIONS: This first fMRI comparison between youth with ASD and with OCD, using a reward-based decision-making task, shows predominantly shared neurofunctional abnormalities during TD in key ventromedial, orbital- and inferior fronto-striatal, temporo-parietal and cerebellar regions of temporal foresight and reward processing, suggesting trans-diagnostic neurofunctional deficits.

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD.

BACKGROUND: Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. METHOD: Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. RESULTS: Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. CONCLUSIONS: The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.

Disorder-dissociated effects of fluoxetine on brain function of working memory in attention deficit hyperactivity disorder and autism spectrum disorder.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are often co-morbid and share performance and brain dysfunctions during working memory (WM). Serotonin agonists modulate WM and there is evidence of positive behavioural effects in both disorders. We therefore used functional magnetic resonance imaging (fMRI) to investigate shared and disorder-specific brain dysfunctions of WM in these disorders, and the effects of a single dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine. METHOD: Age-matched boys with ADHD (n = 17), ASD (n = 17) and controls (n = 22) were compared using fMRI during an N-back WM task. Patients were scanned twice, under either an acute dose of fluoxetine or placebo in a double-blind, placebo-controlled randomized design. Repeated-measures analyses within patients assessed drug effects on performance and brain function. To test for normalization effects of brain dysfunctions, patients under each drug condition were compared to controls. RESULTS: Under placebo, relative to controls, both ADHD and ASD boys shared underactivation in the right dorsolateral prefrontal cortex (DLPFC). Fluoxetine significantly normalized the DLPFC underactivation in ASD relative to controls whereas it increased posterior cingulate cortex (PCC) deactivation in ADHD relative to control boys. Within-patient analyses showed inverse effects of fluoxetine on PCC deactivation, which it enhanced in ADHD and decreased in ASD. CONCLUSIONS: The findings show that fluoxetine modulates brain activation during WM in a disorder-specific manner by normalizing task-positive DLPFC dysfunction in ASD boys and enhancing task-negative default mode network (DMN) deactivation in ADHD.

Ageing diminishes the modulation of human brain responses to visual food cues by meal ingestion.

BACKGROUND/OBJECTIVES: Rates of obesity are greatest in middle age. Obesity is associated with altered activity of brain networks sensing food-related stimuli and internal signals of energy balance, which modulate eating behaviour. The impact of healthy mid-life ageing on these processes has not been characterised. We therefore aimed to investigate changes in brain responses to food cues, and the modulatory effect of meal ingestion on such evoked neural activity, from young adulthood to middle age. SUBJECTS/METHODS: Twenty-four healthy, right-handed subjects, aged 19.5-52.6 years, were studied on separate days after an overnight fast, randomly receiving 50 ml water or 554 kcal mixed meal before functional brain magnetic resonance imaging while viewing visual food cues. RESULTS: Across the group, meal ingestion reduced food cue-evoked activity of amygdala, putamen, insula and thalamus, and increased activity in precuneus and bilateral parietal cortex. Corrected for body mass index, ageing was associated with decreasing food cue-evoked activation of right dorsolateral prefrontal cortex (DLPFC) and precuneus, and increasing activation of left ventrolateral prefrontal cortex (VLPFC), bilateral temporal lobe and posterior cingulate in the fasted state. Ageing was also positively associated with the difference in food cue-evoked activation between fed and fasted states in the right DLPFC, bilateral amygdala and striatum, and negatively associated with that of the left orbitofrontal cortex and VLPFC, superior frontal gyrus, left middle and temporal gyri, posterior cingulate and precuneus. There was an overall tendency towards decreasing modulatory effects of prior meal ingestion on food cue-evoked regional brain activity with increasing age. CONCLUSIONS: Healthy ageing to middle age is associated with diminishing sensitivity to meal ingestion of visual food cue-evoked activity in brain regions that represent the salience of food and direct food-associated behaviour. Reduced satiety sensing may have a role in the greater risk of obesity in middle age.

Drug-specific laterality effects on frontal lobe activation of atomoxetine and methylphenidate in attention deficit hyperactivity disorder boys during working memory.

BACKGROUND: The catecholamine reuptake inhibitors methylphenidate (MPH) and atomoxetine (ATX) are the most common treatments for attention deficit hyperactivity disorder (ADHD). This study compares the neurofunctional modulation and normalization effects of acute doses of MPH and ATX within medication-naive ADHD boys during working memory (WM). METHOD: A total of 20 medication-naive ADHD boys underwent functional magnetic resonance imaging during a parametric WM n-back task three times, under a single clinical dose of either MPH, ATX or placebo in a randomized, double-blind, placebo-controlled, cross-over design. To test for normalization effects, brain activations in ADHD under each drug condition were compared with that of 20 age-matched healthy control boys. RESULTS: Relative to healthy boys, ADHD boys under placebo showed impaired performance only under high WM load together with significant underactivation in the bilateral dorsolateral prefrontal cortex (DLPFC). Both drugs normalized the performance deficits relative to controls. ATX significantly enhanced right DLPFC activation relative to MPH within patients, and significantly normalized its underactivation relative to controls. MPH, by contrast, both relative to placebo and ATX, as well as relative to controls, upregulated the left inferior frontal cortex (IFC), but only during 2-back. Both drugs enhanced fronto-temporo-striatal activation in ADHD relative to control boys and deactivated the default-mode network, which were negatively associated with the reduced DLPFC activation and performance deficits, suggesting compensation effects. CONCLUSIONS: The study shows both shared and drug-specific effects. ATX upregulated and normalized right DLPFC underactivation, while MPH upregulated left IFC activation, suggesting drug-specific laterality effects on prefrontal regions mediating WM.

Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control.

BACKGROUND: What determines inter-individual variability to impairments in behavioural control that may underlie road-traffic accidents, and impulsive and violent behaviours occurring under the influence of cannabis, the most widely used illicit drug worldwide? METHOD: Employing a double-blind, repeated-measures design, we investigated the genetic and neural basis of variable sensitivity to cannabis-induced behavioural dyscontrol in healthy occasional cannabis users. Acute oral challenge with placebo or Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, was combined with functional magnetic resonance imaging, while participants performed a response inhibition task that involved inhibiting a pre-potent motor response. They were genotyped for rs1130233 single nucleotide polymorphisms (SNPs) of the protein kinase B (AKT1) gene. RESULTS: Errors of inhibition were significantly (p = 0.008) increased following administration of THC in carriers of the A allele, but not in G allele homozygotes of the AKT1 rs1130233 SNP. The A allele carriers also displayed attenuation of left inferior frontal response with THC evident in the sample as a whole, while there was a modest enhancement of inferior frontal activation in the G homozygotes. There was a direct relationship (r = -0.327, p = 0.045) between the behavioural effect of THC and its physiological effect in the inferior frontal gyrus, where AKT1 genotype modulated the effect of THC. CONCLUSIONS: These results require independent replication and show that differing vulnerability to acute psychomotor impairments induced by cannabis depends on variation in a gene that influences dopamine function, and is mediated through modulation of the effect of cannabis on the inferior frontal cortex, that is rich in dopaminergic innervation and critical for psychomotor control.

Predicting response to cognitive behavioral therapy in contamination-based obsessive-compulsive disorder from functional magnetic resonance imaging.

BACKGROUND: Although cognitive behavioral therapy (CBT) is an effective treatment for obsessive-compulsive disorder (OCD), few reliable predictors of treatment outcome have been identified. The present study examined the neural correlates of symptom improvement with CBT among OCD patients with predominantly contamination obsessions and washing compulsions, the most common OCD symptom dimension. METHOD: Participants consisted of 12 OCD patients who underwent symptom provocation with contamination-related images during functional magnetic resonance imaging (fMRI) scanning prior to 12 weeks of CBT. RESULTS: Patterns of brain activity during symptom provocation were correlated with a decrease on the Yale-Brown Obsessive Compulsive Scale (YBOCS) after treatment, even when controlling for baseline scores on the YBOCS and the Beck Depression Inventory (BDI) and improvement on the BDI during treatment. Specifically, activation in brain regions involved in emotional processing, such as the anterior temporal pole and amygdala, was most strongly associated with better treatment response. By contrast, activity in areas involved in emotion regulation, such as the dorsolateral prefrontal cortex, correlated negatively with treatment response mainly in the later stages within each block of exposure during symptom provocation. CONCLUSIONS: Successful recruitment of limbic regions during exposure to threat cues in patients with contamination-based OCD may facilitate a better response to CBT, whereas excessive activation of dorsolateral prefrontal regions involved in cognitive control may hinder response to treatment. The theoretical implications of the findings and their potential relevance to personalized care approaches are discussed.

Pattern recognition analysis of anterior cingulate cortex blood flow to classify depression polarity.

Differentiating bipolar from recurrent unipolar depression is a major clinical challenge. In 18 healthy females and 36 females in a depressive episode--18 with bipolar disorder type I, 18 with recurrent unipolar depression--we applied pattern recognition analysis using subdivisions of anterior cingulate cortex (ACC) blood flow at rest, measured with arterial spin labelling. Subgenual ACC blood flow classified unipolar v. bipolar depression with 81% accuracy (83% sensitivity, 78% specificity).

Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab.

BACKGROUND: Pertuzumab, a human epidermal growth factor receptor (HER) 2 dimerization inhibitor, has demonstrated promising efficacy in combination with trastuzumab in patients with metastatic breast cancer. As HER signaling pathways are not only involved in oncogenesis, but also in myocardial homeostasis, an analysis of cardiac safety data was undertaken in a large group of patients treated with pertuzumab. PATIENTS AND METHODS: A complete database of patients treated with full-dose pertuzumab was used to describe the incidence of asymptomatic left ventricular systolic dysfunction (LVSD) and symptomatic heart failure (HF). RESULTS: Information for 598 unique patients was available for the current analysis. Of the patients treated with pertuzumab alone (n = 331) or pertuzumab in combination with a non-anthracycline-containing cytotoxic (n = 175) or trastuzumab (n = 93), 23 (6.9%), 6 (3.4%), and 6 (6.5%), respectively, developed asymptomatic LVSD and 1 (0.3%), 2 (1.1%), and 1 (1.1%), respectively, displayed symptomatic HF. None of the 15 patients receiving both pertuzumab and erlotinib demonstrated LVSD. CONCLUSIONS: Patients treated with pertuzumab experienced relatively low levels of asymptomatic LVSD or symptomatic HF. There was no notable increase in cardiac side-effects when pertuzumab was given in combination with other anticancer agents.

The functional neuroanatomy of blood-injection-injury phobia: a comparison with spider phobics and healthy controls.

BACKGROUND: Most neuroimaging studies of specific phobia have investigated the animal subtype. The blood-injection-injury (BII) subtype is characterized by a unique biphasic psychophysiological response, which could suggest a distinct neural substrate, but direct comparisons between phobia types are lacking. METHOD: This study compared the neural responses during the presentation of phobia-specific stimuli in 12 BII phobics, 14 spider (SP) phobics and 14 healthy controls using functional magnetic resonance imaging (fMRI). RESULTS: Subjective ratings showed that the experimental paradigm produced the desired symptom-specific effects. As in many previous studies, when viewing spider-related stimuli, SP phobics showed increased activation in dorsal anterior cingulate and anterior insula, compared to BII phobics and healthy controls. However, when viewing images of blood-injection-injuries, participants with BII phobia mainly showed increased activation in the thalamus and visual/attention areas (occipito-temporo-parietal cortex), compared with the other two groups. The degree of provoked anxiety and disgust by phobia-relevant images was strongly associated with activation in several common regions across the two phobia groups (thalamus, cerebellum, occipito-temporal regions) but only correlated with activation in the dorsal anterior cingulate gyrus and the anterior insula in the SP phobics. CONCLUSIONS: These results suggest partially distinct neurobiological substrates of animal and BII phobias and support their current classification as two distinct subtypes in the DSM-IV-TR. Further research is needed to better understand the precise neurobiological mechanisms in BII phobia and particularly the fainting response.

Clinical and anatomical heterogeneity in autistic spectrum disorder: a structural MRI study.

BACKGROUND: Autistic spectrum disorder (ASD) is characterized by stereotyped/obsessional behaviours and social and communicative deficits. However, there is significant variability in the clinical phenotype; for example, people with autism exhibit language delay whereas those with Asperger syndrome do not. It remains unclear whether localized differences in brain anatomy are associated with variation in the clinical phenotype. METHOD: We used voxel-based morphometry (VBM) to investigate brain anatomy in adults with ASD. We included 65 adults diagnosed with ASD (39 with Asperger syndrome and 26 with autism) and 33 controls who did not differ significantly in age or gender. RESULTS: VBM revealed that subjects with ASD had a significant reduction in grey-matter volume of medial temporal, fusiform and cerebellar regions, and in white matter of the brainstem and cerebellar regions. Furthermore, within the subjects with ASD, brain anatomy varied with clinical phenotype. Those with autism demonstrated an increase in grey matter in frontal and temporal lobe regions that was not present in those with Asperger syndrome. CONCLUSIONS: Adults with ASD have significant differences from controls in the anatomy of brain regions implicated in behaviours characterizing the disorder, and this differs according to clinical subtype.

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.

To discard or not to discard: the neural basis of hoarding symptoms in obsessive-compulsive disorder.

Preliminary neuroimaging studies suggest that patients with the 'compulsive hoarding syndrome' may be a neurobiologically distinct variant of obsessive-compulsive disorder (OCD) but further research is needed. A total of 29 OCD patients (13 with and 16 without prominent hoarding symptoms) and 21 healthy controls of both sexes participated in two functional magnetic resonance imaging experiments consisting of the provocation of hoarding-related and symptom-unrelated (aversive control) anxiety. In response to the hoarding-related (but not symptom-unrelated) anxiety provocation, OCD patients with prominent hoarding symptoms showed greater activation in bilateral anterior ventromedial prefrontal cortex (VMPFC) than patients without hoarding symptoms and healthy controls. In the entire patient group (n=29), provoked anxiety was positively correlated with activation in a frontolimbic network that included the anterior VMPFC, medial temporal structures, thalamus and sensorimotor cortex. Negative correlations were observed in the left dorsal anterior cingulate gyrus, bilateral temporal cortex, bilateral dorsolateral/medial prefrontal regions, basal ganglia and parieto-occipital regions. These results were independent from the effects of age, sex, level of education, state anxiety, depression, comorbidity and use of medication. The findings are consistent with the animal and lesion literature and several landmark clinical features of compulsive hoarding, particularly decision-making difficulties. Whether the results are generalizable to hoarders who do not meet criteria for OCD remains to be investigated.

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.

Galactocerebroside is expressed by non-myelin-forming Schwann cells in situ.

Interest in the glycosphingolipid galactocerebroside (GC) is based on the consensus that in the nervous system it is expressed only by myelin-forming Schwann cells and oligodendrocytes, and that it has a specific role in the elaboration of myelin sheaths. We have investigated GC distribution in two rat nerves--the sciatic, containing a mixture of myelinated and non-myelinated axons, and the cervical sympathetic trunk, in which greater than 99% of axons are non-myelinated. Immunohistochemical experiments using mono- and polyclonal GC antibodies were carried out on teased nerves and cultured Schwann cells, and GC synthesis was assayed biochemically. Unexpectedly, we found that mature non-myelin-forming Schwann cells in situ and in short-term cultures express unambiguous GC immunoreactivity, comparable in intensity to that of myelinated fibers or myelin-forming cells in short-term cultures. GC synthesis was also detected in both sympathetic trunks and sciatic nerves. In the developing sympathetic trunk, GC was first seen at day 19 in utero, the number of GC-positive cells rising to approximately 95% at postnatal day 10. In contrast, the time course of GC appearance in the sciatic nerve shows two separate phases of increase, between day 18 in utero and postnatal day 1, and between postnatal days 20 and 35, at which stage approximately 94% of the cells express GC. These time courses suggest that Schwann cells, irrespective of subsequent differentiation pathway, start expressing GC at about the same time as cell division stops. We suggest that GC is a ubiquitous component of mature Schwann cell membranes in situ. Therefore, the role of GC needs to be reevaluated, since its function is clearly not restricted to events involved in myelination.

Activation of auditory cortex during silent lipreading.

Watching a speaker's lips during face-to-face conversation (lipreading) markedly improves speech perception, particularly in noisy conditions. With functional magnetic resonance imaging it was found that these linguistic visual cues are sufficient to activate auditory cortex in normal hearing individuals in the absence of auditory speech sounds. Two further experiments suggest that these auditory cortical areas are not engaged when an individual is viewing nonlinguistic facial movements but appear to be activated by silent meaningless speechlike movements (pseudospeech). This supports psycholinguistic evidence that seen speech influences the perception of heard speech at a prelexical stage.

The interactive effect of the cholinergic system and acute ovarian suppression on the brain: an fMRI study.

Recent evidence suggests that loss of ovarian function following ovariectomy is a risk factor for Alzheimer's disease (AD); however, the biological basis of this risk remains poorly understood. We carried out an fMRI study into the interaction between loss of ovarian function (after Gonadotropin Hormone Releasing Hormone agonist (GnRHa) treatment) and scopolamine (a cholinergic antagonist used to model the memory decline associated with aging and AD). Behaviorally, cholinergic depletion produced a deficit in verbal recognition performance in both GnRHa-treated women and wait list controls, but only GnRHa-treated women made more false positive errors with cholinergic depletion. Similarly, cholinergic depletion produced a decrease in activation in the left inferior frontal gyrus (LIFG; Brodmann area 45)--a brain region implicated in retrieving word meaning--in both groups, and activation in this area was further reduced following GnRHa treatment. These findings suggest biological mechanisms through which ovarian hormone suppression may interact with the cholinergic system and the LIFG. Furthermore, this interaction may provide a useful model to help explain reports of increased risk for cognitive decline and AD in women following ovariectomy.

Neural markers of symptomatic improvement during antidepressant therapy in severe depression: subgenual cingulate and visual cortical responses to sad, but not happy, facial stimuli are correlated with changes in symptom score.

Resting state activity in the ventral cingulate may be an important neural marker of symptomatic improvement in depression. The number of task related functional magnetic resonance imaging (fMRI) studies correlating blood oxygenation level dependent (BOLD) response with symptomatic improvement is limited and methodologies are still evolving. We measured BOLD responses to sad and happy facial stimuli in 12 severely depressed individuals in the early stages of antidepressant treatment (Time 1) and 12 weeks later (Time 2) using event-related fMRI. We calculated correlations between temporal changes in BOLD response and changes in symptom scores. Most subjects improved markedly by Time 2. At Time 1, depression severity correlated positively with responses to sad stimuli in the right visual cortex, subgenual cingulate, anterior temporal pole and hippocampus and correlated negatively with responses to happy stimuli in left visual cortex and right caudate. Decreases in individual effect sizes of right subgenual cingulate and right visual cortical responses to sad, but not happy, facial stimuli were correlated with decreases in symptom scores. There are contrasting cortical and subcortical responses to sad and happy stimuli in severe depression. Responses to sad stimuli show the strongest correlates of clinical improvement, particularly in the subgenual cingulate.