When less is more: a functional magnetic resonance imaging study of verbal working memory in remitted depressed patients.

BACKGROUND: Patients with depression show abnormalities in the neural circuitry supporting working memory. However, it is unclear if these abnormalities are present in unmedicated remitted depressed patients. To address this question, the current study employed functional magnetic resonance imaging (fMRI), in combination with a simple verbal n-back task, in a cohort of unmedicated remitted depressed patients. METHOD: We studied 15 healthy control subjects (HC) and 15 unmedicated remitted depressed patients (rMDD). Participants performed a verbal working memory task of varying cognitive load (n-back) while undergoing fMRI. We used multiple regression analyses to assess overall capacity (1-, 2-, 3-back versus 0-back) as well as quadratic modulation of cognitive demand. RESULTS: Performance accuracy and response latency did not differ between groups, and overall capacity was similar. However, rMDD showed a positive quadratic load response in the bilateral hippocampus; the converse was true for HC. CONCLUSIONS: Our data suggest that remitted depression was associated with a perturbed pattern of activation in the bilateral hippocampus during a verbal working memory task. We propose that a reduced ability to dampen task-irrelevant activity may reflect a neurobiological risk factor for recurrent depression.

Paradoxical effects of short-term antidepressant treatment in fMRI emotional processing models in volunteers with high neuroticism.

BACKGROUND: Short-term antidepressant administration has been reported to decrease amygdala response to threat in healthy volunteers and depressed patients. Neuroticism (N) is a risk factor for depression but has also been associated with slow or incomplete remission with antidepressant drug treatment. Our aim was to investigate early selective serotonin reuptake inhibitor (SSRI) administration neural effects on implicit processing of fearful facial expressions in volunteers with high levels of N. METHOD: Highly neurotic subjects received 20 mg/day citalopram versus placebo for 7 days in a double-blind, between-groups design. On the last day haemoperfusion and functional magnetic resonance imaging (fMRI) data during a gender discrimination task with fearful and happy faces were acquired. A control group of non-neurotic volunteers was also tested. RESULTS: High-N volunteers had reduced responses to threatening facial expressions across key neural circuits compared to low-N volunteers. SSRI treatment was found to elevate resting perfusion in the right amygdala, increase bilateral amygdalae activation to positive and negative facial expressions and increase activation to fearful versus happy facial expressions in occipital, parietal, temporal and prefrontal cortical areas. CONCLUSIONS: These results suggest that 7 days of SSRI administration can increase neural markers of fear reactivity in subjects at the high end of the N dimension and may be related to early increases in anxiety and agitation seen early in treatment. Such processes may be involved in the later therapeutic effects through decreased avoidance and increased learning about social 'threat' cues.

The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a meta-analysis.

The 5-HTTLPR polymorphism has been widely regarded as a potential genetic risk factor for affective disorders. Consistent with this, this polymorphism has been associated with altered amygdala responses at rest and in response to aversive stimuli. However, the strength of this association remains uncertain. We sought to synthesize existing data on the association between the 5-HTTLPR polymorphism and amygdala activation and ascertain the strength of evidence for this association. Meta-analytic techniques were applied to data from relevant published studies and unpublished data sets to obtain an estimate of the likely magnitude of effect of any association. The large number of studies allowed us to apply a formal test of publication bias, as well as explore the impact of various study-level characteristics on the magnitude of the observed effect size. Our meta-analysis indicated that there is a statistically significant but small effect of 5-HTTLPR on left and right amygdala activity. However, there was considerable between-study heterogeneity, which could not be fully accounted for by the study design and sample characteristics that we investigated. In addition, there was evidence of excess statistical significance among published studies. These findings indicate that the association between the 5-HTTLPR and amygdala activation is smaller than originally thought, and that the majority of previous studies have been considerably under powered to reliably demonstrate an effect of this size.

Short-term antidepressant administration reduces negative self-referential processing in the medial prefrontal cortex in subjects at risk for depression.

Depression has been associated with changes in responses within the medial prefrontal cortex (mPFC) during emotional information processing. Antidepressant drug treatment has been shown to modify neural responses in healthy volunteers early in treatment within similar circuitry. It is unclear, however, whether the same early effect occurs in depressed patients, before changes in mood. The current study therefore investigated the effects of 7-days administration of the selective serotonin-uptake inhibitor citalopram vs placebo in volunteers (n=29) at a high risk for the development of depression, using the personality phenotype of high neuroticism in a double-blind, between-groups design. On the last day of treatment, resting haemoperfusion and functional magnetic resonance imaging (MRI) data were acquired during a self-referential words categorisation task. A significant activation in a cluster of mPFC areas, including dorsal anterior cingulate and right orbitofrontal cortex was revealed, driven by decreased responses to the negative self-descriptors following citalopram compared with placebo, in the absence of any mood differences. These findings show a normalisation of neural abnormalities in- and at-risk population early in treatment, supporting the theory that antidepressants may indeed act by modifying specific neural dysfunctions correlated to negative cognitive biases.

Short-term SSRI treatment normalises amygdala hyperactivity in depressed patients.

BACKGROUND: Antidepressant drugs such as selective serotonin re-uptake inhibitors (SSRIs) remediate negative biases in emotional processing in depressed patients in both behavioural and neural outcome measures. However, it is not clear if these effects occur before, or as a consequence of, changes in clinical state. METHOD: In the present study, we investigated the effects of short-term SSRI treatment in depressed patients on the neural response to fearful faces prior to clinical improvement in mood. Altogether, 42 unmedicated depressed patients received SSRI treatment (10 mg escitalopram daily) or placebo in a randomised, parallel-group design. The neural response to fearful and happy faces was measured on day 7 of treatment using functional magnetic resonance imaging. A group of healthy controls was imaged in the same way. RESULTS: Amygdala responses to fearful facial expressions were significantly greater in depressed patients compared to healthy controls. However, this response was normalised in patients receiving 7 days treatment with escitalopram. There was no significant difference in clinical depression ratings at 7 days between the escitalopram and placebo-treated patients. CONCLUSIONS: Our results suggest that short-term SSRI treatment in depressed patients remediates amygdala hyperactivity in response to negative emotional stimuli prior to clinical improvement in depressed mood. This supports the hypothesis that the clinical effects of antidepressant treatment may be mediated in part through early changes in emotional processing. Further studies will be needed to show if these early effects of antidepressant medication predict eventual clinical outcome.

Neural response to angry and disgusted facial expressions in bulimia nervosa.

BACKGROUND: Processing emotional facial expressions is of interest in eating disorders (EDs) as impairments in recognizing and understanding social cues might underlie the interpersonal difficulties experienced by these patients. Disgust and anger are of particular theoretical and clinical interest. The current study investigated the neural response to facial expressions of anger and disgust in bulimia nervosa (BN). METHOD: Participants were 12 medication-free women with BN in an acute episode (mean age 24 years), and 16 age-, gender- and IQ-matched healthy volunteers (HVs). Functional magnetic resonance imaging (fMRI) was used to examine neural responses to angry and disgusted facial expressions. RESULTS: Compared with HVs, patients with BN had a decreased neural response in the precuneus to facial expressions of both anger and disgust and a decreased neural response to angry facial expressions in the right amygdala. CONCLUSIONS: The neural response to emotional facial expressions in BN differs from that found in HVs. The precuneus response may be consistent with the application of mentalization theory to EDs, and the amygdala response with relevant ED theory. The findings are preliminary, but novel, and require replication in a larger sample.

Increased neural response to fear in patients recovered from depression: a 3T functional magnetic resonance imaging study.

BACKGROUND: Previous imaging studies have revealed that acute major depression is characterized by altered neural responses to negative emotional stimuli. Typically, responses in limbic regions such as the amygdala are increased while activity in cortical regulatory regions such as the dorsolateral prefrontal cortex (DLPFC) is diminished. Whether these changes persist in unmedicated recovered patients is unclear. METHOD: We used functional magnetic resonance imaging to examine neural responses to emotional faces in a facial expression-matching task in 16 unmedicated recovered depressed patients and 21 healthy controls. RESULTS: Compared with controls, recovered depressed patients had increased responses bilaterally to fearful faces in the DLPFC and right caudate. Responses in the amygdala did not distinguish the groups. CONCLUSIONS: Our findings indicate that clinical recovery from depression is associated with increased activity in the DLPFC to negative emotional stimuli. We suggest that this increase may reflect a compensatory cortical control mechanism with the effect of limiting emotional dysregulation in limbic regions such as the amygdala.

The effects of reboxetine on emotional processing in healthy volunteers: an fMRI study.

Recent neuropsychological studies in healthy volunteers suggest that antidepressants enhance the processing of positive emotional information. However, the neural substrates underpinning these changes have not been fully elucidated. The current study, therefore, used functional magnetic resonance imaging (fMRI) to map brain systems activated during successful categorization and subsequent recognition of self-referent positive and negative personality characteristics in healthy volunteers following short-term (7 days) repeated administration of the selective noradrenergic reuptake inhibitor reboxetine. Twenty-four healthy volunteers were randomly assigned to 7-day double-blind intervention with reboxetine or placebo. On day 7, neural responses during the categorization and subsequent recognition of positive and negative characteristics were assessed using fMRI. Questionnaires monitoring mood, hostility and anxiety were given before and during this intervention. During categorization, reboxetine was associated with greater activation to positive words, relative to negative words, in left precuneus and right inferior frontal gyrus. By contrast, at subsequent recognition reboxetine was associated with reduced response to positive words, relative to negative words, in left precuneus, anterior cingulate and medial frontal gyrus. These changes in the neural processing of positive and negative words occurred in the absence of significant differences in ratings of mood and anxiety. Such adaptations in the neural processing of emotional information support the hypothesis that antidepressants have early effects on emotional processing in a manner which would be expected to reverse negative biases in depression.

Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression.

Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.

In vivo imaging of muscarinic receptors in the aging female brain with (R,R)[123I]-I-QNB and single photon emission tomography.

The effect of age on brain muscarinic receptor density is unclear. Some in vivo neuroimaging studies have reported a large age-related reduction in muscarinic receptor density; however, others have reported increases or no change. The variability in these results most likely arises because of the heterogeneity of the populations studied, differences in quantification methods employed, and a paucity of subtype selective ligands. Thus, we used the m(1)/m(4) selective probe (R,R)[(123)I]-I-QNB to investigate age-related differences in brain muscarinic receptors in healthy females. We included 10 younger subjects (age range 26-37) and 22 older women (age range 57-82 years). The older women had significantly lower (R,R)[(123)I]-I-QNB binding in widespread brain regions including cerebral cortex and hippocampus. Across all subjects, regional binding was significantly negatively correlated with age. Thus, in this population of healthy women, there was an age-related reduction in muscarinic receptor density. This may contribute to age-related differences in cognitive function and risk for Alzheimer's disease.

ß-Adrenoceptor blockade modulates fusiform gyrus activity to black versus white faces.

INTRODUCTION: The beta-adrenoceptor antagonist propranolol is known to reduce peripheral and central activity of noradrenaline. A recent study found that intervention with propranolol diminished negative implicit racial bias. MATERIALS AND METHOD: The current study used functional magnetic resonance imaging (fMRI) in order to determine the neural correlates of this effect. Healthy volunteers (N = 40) of white ethnic origin received a single oral dose (40 mg) of propranolol, in a randomised, double-blind, parallel group, placebo-controlled design, before viewing unfamiliar faces of same and other race. RESULTS AND DISCUSSION: We found significantly reduced activity in the fusiform gyrus and thalamus following propranolol to out-group faces only. Additionally, propranolol lowered the implicit attitude score, without affecting explicit prejudice measure. CONCLUSION: These findings suggest that noradrenaline pathways might modulate racial bias by acting on the processing of categorisation in the fusiform gyrus.

SPET imaging of central muscarinic receptors with (R,R)[123I]-I-QNB: methodological considerations.

Investigations on the effect of normal healthy ageing on the muscarinic system have shown conflicting results. Also, in vivo determination of muscarinic receptor binding has been hampered by a lack of subtype selective ligands and differences in methods used for quantification of receptor densities. Recent in vitro and in vivo work with the muscarinic antagonist (R,R)-I-QNB indicates this ligand has selectivity for m(1) and m(4) muscarinic receptor subtypes. Therefore, we used (R,R)[(123)I]-I-QNB and single photon emission tomography to study brain m(1) and m(4) muscarinic receptors in 25 healthy female subjects (11 younger subjects, age range 26-32 years and 14 older subjects, age range 57-82 years). Our aims were to ascertain the viability of tracer administration and imaging within the same day, and to evaluate whether normalization to whole brain, compared to normalization to cerebellum, could alter the clinical interpretation of results. Images were analyzed using the simplified reference tissue model and by two ratio methods: normalization to whole brain and normalization to cerebellum. Significant correlations were observed between kinetic analysis and normalization to cerebellum, but not to whole brain. Both the kinetic analysis and normalization to cerebellum showed age-related reductions in muscarinic binding in frontal, orbitofrontal, and parietal regions. Normalization to whole brain, however, failed to detect age-related changes in any region. Here we show that, for this radiotracer, normalizing to a region of negligible specific binding (cerebellum) significantly improves sensitivity when compared to global normalization.

Neural correlates of the processing of self-referent emotional information in bulimia nervosa.

There is increasing interest in understanding the roles of distorted beliefs about the self, ostensibly unrelated to eating, weight and shape, in eating disorders (EDs), but little is known about their neural correlates. We therefore used functional magnetic resonance imaging to investigate the neural correlates of self-referent emotional processing in EDs. During the scan, unmedicated patients with bulimia nervosa (n=11) and healthy controls (n=16) responded to personality words previously found to be related to negative self beliefs in EDs and depression. Rating of the negative personality descriptors resulted in reduced activation in patients compared to controls in parietal, occipital and limbic areas including the amygdala. There was no evidence that reduced activity in patients was secondary to increased cognitive control. Different patterns of neural activation between patients and controls may be the result of either habituation to personally relevant negative self beliefs or of emotional blunting in patients.

Lack of effect of citalopram on magnetic resonance spectroscopy measures of glutamate and glutamine in frontal cortex of healthy volunteers.

Magnetic resonance spectroscopy (MRS) is a non-invasive imaging technique that can provide localised measures of brain chemistry in vivo. We previously found that healthy volunteers receiving the selective serotonin reuptake inhibitor, citalopram, daily for 1 week showed higher levels of a combined measure of glutamate and glutamine (Glx) in occipital cortex than those receiving placebo. The aim of this study was to assess if a similar effect could be detected in the frontal brain region. Twenty-three healthy volunteers randomised to receive either citalopram 20 mg or a placebo capsule daily for 7-10 days were studied and scanned using a 3T Varian INOVA system before and at the end of treatment. Standard short-TE (echo time) PRESS (Point-resolved spectroscopy) (TE = 26 ms) and PRESS-J spectra were acquired from a single 8-cm(3) voxel in a frontal region incorporating anterior cingulate cortex. Glutamate and total Glx levels were quantified both relative to creatine and as absolute levels. Relative to placebo, citalopram produced no change in Glx or glutamate alone at the end of the study. Similarly, no effect was seen on other MRS measures studied: myo-inositol, choline, N-acetylaspartate and creatine. These data suggest that the effects of serotonin reuptake to modify cortical glutamatergic MRS measures may be regionally specific. This supports the potential for MRS in assessing neuroanatomically specific serotonin-glutamate interactions in the human brain.

Long-term estrogen therapy and 5-HT(2A) receptor binding in postmenopausal women; a single photon emission tomography (SPET) study.

Variation in estrogen level is reported by some to affect brain maturation and memory. The neurobiological basis for this may include modulation of the serotonergic system. No neuroimaging studies have directly examined the effect of extended estrogen therapy (ET), on the 5-HT(2A) receptor in human brain. We investigated the effect of long-term ET on cortical 5-HT(2A) receptor availability in postmenopausal women. In a cross-sectional study, we compared cortical 5-HT(2A) receptor availability in 17 postmenopausal ERT-naive women and 17 long-term oophorectomised estrogen-users, age- and IQ-matched using single photon emission tomography and the selective 5-HT(2A) receptor ligand (123)I-5-I-R91150. Also, we used the Revised Wechsler Memory Scale to relate memory function to 5-HT(2A) receptor availability. Never-users had significantly higher 5-HT(2A) receptor availability than estrogen-users in hippocampus (1.17 vs. 1.11, respectively, p=0.02), although this did not remain significant after correction for multiple comparisons. Hippocampal 5-HT(2A) receptor availability correlated negatively with verbal and general memory and delayed recall (r=-0.45, p=0.01; r=-0.40, p=0.02; r=-0.36, p=0.04). Right superior temporal 5-HT(2A) receptor availability correlated negatively with verbal memory (r=-0.36, p=0.04). In estrogen-users, receptor availability correlated negatively with verbal and general memory (r=-0.70, p=0.002; r=-0.69, p=0.002); and in never-users, receptor availability negatively correlated with attention and concentration (r=-0.54, p=0.02). Long-term ET may be associated with lower 5-HT(2A) receptor availability in hippocampus. This may reflect increased activity within the serotonergic pathway leading to down-regulation of post-synaptic receptor. Also, increased availability of the 5-HT(2A) receptor in hippocampus is associated with poorer memory function.

Congenital microvillous inclusion disease presenting as antenatal bowel obstruction.

Prenatal ultrasound has led to confidence in the antenatal diagnosis of intestinal obstruction allowing counseling and birth planning. We describe a male infant of a diabetic mother who had an antenatal diagnosis of distal bowel obstruction. This baby was subsequently found not to have bowel obstruction, but a congenital enteropathy - microvillous inclusion disease. The antenatal scans had demonstrated polyhydramnios as well as multiple fluid-filled dilated loops of bowel in the fetal abdomen. To our knowledge, similar prenatal ultrasound findings have not been previously described in this condition. The baby was delivered in a pediatric surgical center and postnatally there was no evidence of bowel obstruction either clinically or on abdominal X-ray. This baby initially fed well, but became collapsed and acidotic on his third day, having lost 26% of his birth weight due to excessive stool loss. The diagnosis of microvillous inclusion disease was made by electron microscopy of a small bowel biopsy. Congenital microvillous inclusion disease is a very rare inherited enteropathy with high mortality and morbidity. This condition, and other enteropathies, should be considered in cases in which antenatally diagnosed bowel obstruction is not confirmed after birth.