Recognition memory is associated with altered resting‐state functional connectivity in people at genetic risk for Alzheimer's disease

The apolipoprotein E ε4 (ApoE ε4) allele not only represents the strongest single genetic risk factor for sporadic Alzheimer's disease, but also imposes independent effects on brain function in healthy individuals where it has been shown to promote subtle memory deficits and altered intrinsic functional brain network connectivity. Based on previous work showing a potential relevance of the default mode network (DMN) functional connectivity for episodic memory function, we hypothesized that the ApoE ε4 genotype would affect memory performance via modulation of the DMN. We assessed 63 healthy individuals (50–80 years old), of which 20 carried the ε4 allele. All participants underwent resting‐state functional magnetic resonance imaging (fMRI), high‐resolution 3D anatomical MRI imaging and neuropsychological assessment. Functional connectivity analysis of resting‐state activity was performed with a predefined seed region located in the left posterior cingulate cortex (PCC), a core region of the DMN. ApoE ε4 carriers performed significantly poorer than non‐carriers in wordlist recognition and cued recall. Furthermore, ε4 carriers showed increased connectivity relative to ε4 non‐carriers between the PCC seed region and left‐hemispheric middle temporal gyrus (MTG). There was a positive correlation between recognition memory scores and resting‐state connectivity in the left MTG in ε4 carriers. These results can be interpreted as compensatory mechanisms strengthening the cross‐links between DMN core areas and cortical areas involved in memory processing.     

The spatio‐temporal profile of multisensory integration

Task‐irrelevant visual stimuli can enhance auditory perception. However, while there is some neurophysiological evidence for mechanisms that underlie the phenomenon, the neural basis of visually induced effects on auditory perception remains unknown. Combining fMRI and EEG with psychophysical measurements in two independent studies, we identified the neural underpinnings and temporal dynamics of visually induced auditory enhancement. Lower‐ and higher‐intensity sounds were paired with a non‐informative visual stimulus, while participants performed an auditory detection task. Behaviourally, visual co‐stimulation enhanced auditory sensitivity. Using fMRI, enhanced BOLD signals were observed in primary auditory cortex for low‐intensity audiovisual stimuli which scaled with subject‐specific enhancement in perceptual sensitivity. Concordantly, a modulation of event‐related potentials could already be observed over frontal electrodes at an early latency (30–80 ms), which again scaled with subject‐specific behavioural benefits. Later modulations starting around 280 ms, that is in the time range of the P3, did not fit this pattern of brain‐behaviour correspondence. Hence, the latency of the corresponding fMRI‐EEG brain‐behaviour modulation points at an early interplay of visual and auditory signals in low‐level auditory cortex, potentially mediated by crosstalk at the level of the thalamus. However, fMRI signals in primary auditory cortex, auditory thalamus and the P50 for higher‐intensity auditory stimuli were also elevated by visual co‐stimulation (in the absence of any behavioural effect) suggesting a general, intensity‐independent integration mechanism. We propose that this automatic interaction occurs at the level of the thalamus and might signify a first step of audiovisual interplay necessary for visually induced perceptual enhancement of auditory perception.     

A genome‐wide supported psychiatric risk variant in NCAN influences brain function and cognitive performance in healthy subjects

The A allele of the single nucleotide polymorphism (SNP) rs1064395 in the NCAN gene has recently been identified as a susceptibility factor for bipolar disorder and schizophrenia. NCAN encodes neurocan, a brain‐specific chondroitin sulfate proteoglycan that is thought to influence neuronal adhesion and migration. Several lines of research suggest an impact of NCAN on neurocognitive functioning. In the present study, we investigated the effects of rs1064395 genotype on neural processing and cognitive performance in healthy subjects. Brain activity was measured with functional magnetic resonance imaging (fMRI) during an overt semantic verbal fluency task in 110 healthy subjects who were genotyped for the NCAN SNP rs1064395. Participants additionally underwent comprehensive neuropsychological testing. Whole brain analyses revealed that NCAN risk status, defined as AA or AG genotype, was associated with a lack of task‐related deactivation in a large left lateral temporal cluster extending from the middle temporal gyrus to the temporal pole. Regarding neuropsychological measures, risk allele carriers demonstrated poorer immediate and delayed verbal memory performance when compared to subjects with GG genotype. Better verbal memory performance was significantly associated with greater deactivation of the left temporal cluster during the fMRI task in subjects with GG genotype. The current data demonstrate that common genetic variation in NCAN influences both neural processing and cognitive performance in healthy subjects. Our study provides new evidence for a specific genetic influence on human brain function. Hum Brain Mapp, 36:378–390, 2015. © 2014 Wiley Periodicals, Inc.     

The Drosophila Kctd‐family homologue Kctd12‐like modulates male aggression and mating behaviour

In Drosophila, serotonin (5‐HT) regulates aggression, mating behaviour and sleep/wake behaviour through different receptors. Currently, how these various receptors are themselves regulated is still not completely understood. The KCTD12‐family of proteins, which have been shown to modify G‐protein‐coupled receptor (GPCR) signalling in mammals, are one possibility of auxiliary proteins modulating 5‐HT receptor signalling. The KCTD12‐family was found to be remarkably conserved and present in species from C. elegans to humans. The Drosophila KCTD12 homologue Kctd12‐like (Ktl) was highly expressed in both the larval and adult CNS. By performing behavioural assays in male Drosophila, we now reveal that Ktl is required for proper male aggression and mating behaviour. Previously, it was shown that Ktl is in a complex with the Drosophila 5‐HT receptor 5‐HT7, and we observed that both Ktl and the 5‐HT1A receptor are required in insulin‐producing cells (IPCs) for proper adult male behaviour, as well as for hyperaggressive activity induced by the mammalian 5‐HT1A receptor agonist 8‐hydroxy‐2‐dipropylaminotetralin‐hydrobromide. Finally, we show that Ktl expression in the IPCs is necessary to regulate locomotion and normal sleep/wake patterns in Drosophila, but not the 5‐HT1A receptor. Similar to what was observed with mammalian KCTD12‐family members that interact physically with a GPCR receptor to regulate desensitization, in Drosophila Ktl may function in GPCR 5‐HT receptor pathways to regulate their signalling, which is required for proper adult male behaviour.     

Reduced memory in fat mass and obesity‐associated allele carriers among older adults with cardiovascular disease

Background: Much attention has been paid to the prevalence and predisposition of the fat mass and obesity‐associated (FTO) gene to obesity, although only a few studies have characterized the extent to which this affects cognitive function. This study examined differences between risk allele carriers (i.e. FTO‐AC/AA) and non‐carriers (i.e. FTO‐CC) on indices of attention/executive function/psychomotor speed, memory, language, and visual‐spatial ability in a sample of older patients with cardiovascular disease. Methods: We recruited 120 older adults from an outpatient cardiology clinic who underwent blood draw and completed neuropsychological testing. Participants were classified into two groups: one for those who were homozygous for the non‐risk‐conferring allele (i.e. FTO‐CC) (n= 49) and the other for those who had at least one copy of the obesity risk‐conferring A allele (i.e. FTO‐AC/AA) (n= 71). Results: Mancova analyses adjusting for age and years of education revealed the FTO‐AC/AA group performed significantly worse on indices of memory (λ= 0.94, F(2, 115) = 3.58, P= 0.03, partial η²= 0.06). Follow‐up tests revealed a significant effect for the FTO‐AC/AA group, relative to the non‐carrier group, on encoding (i.e. California Verbal Learning Test Total Learning) and California Verbal Learning Test long‐delay free recall (P < 0.05). No such differences between FTO carriers and non‐carriers emerged on tests of attention/executive function/psychomotor speed, language, or visual‐spatial ability (P > 0.05 for all). Conclusions: These findings suggest that the FTO risk allele is associated with reduced memory performance, particularly on aspects of memory encoding and delayed recall. To elucidate underlying mechanisms, these findings will need to be replicated in larger samples that utilize neuroimaging.     

Long‐term,calorie‐restricted intake of a high‐fat diet in rats reduces impulse control and ventral striatal D2 receptor signalling – two markers of addiction vulnerability

High impulsivity, mediated through ventral striatal dopamine signalling, represents an established risk factor for substance abuse, and may likewise confer vulnerability to pathological overeating. Mechanistically, the assumption is that trait impulsivity facilitates the initiation of maladaptive eating styles or choices. However, whether consumption of appetitive macronutrients themselves causes deficits in impulse control and striatal signalling, thereby contributing to cognitive changes permissive of overeating behaviour, has yet to be considered. We examined the effects of chronic maintenance on restricted equicaloric, but high‐fat or high‐sugar, diets (48 kcal/day; 60 kcal% fat or sucrose) on rats’ performance in the five‐choice serial reaction time task, indexing impulsivity and attention. Markers of dopamine signalling in the dorsal and ventral striatum, and plasma insulin and leptin levels, were also assessed. Rats maintained on the high‐fat diet (HFD) were more impulsive, whereas the high‐sugar diet (HSD) did not alter task performance. Importantly, body weight and hormone levels were similar between groups when behavioural changes were observed. Maintenance on HFD, but not on HSD, reduced the levels of dopamine D₂ receptor (D₂R), cAMP response element‐binding protein (CREB) and phosphophorylated CREB (Ser133) proteins in the ventral, but not dorsal, striatum. D₂R expression in the ventral striatum also negatively correlated with impulsive responding, independently of diet. These data indicate that chronic exposure to even limited amounts of high‐fat foods may weaken impulse control and alter neural signalling in a manner associated with vulnerability to addictions – findings that have serious implications for the propagation of uncontrolled eating behaviour in obesity and binge‐eating disorder.     

Neurochemical correlates of scene processing in the precuneus/posterior cingulate cortex: A multimodal fMRI and 1H‐MRS study

Precuneus/posterior cingulate cortex (PCu/PCC) are key components of a midline network, activated during rest but also in tasks that involve construction of scene or situation models. Despite growing interest in PCu/PCC functional alterations in disease and disease risk, the underlying neurochemical modulators of PCu/PCC's task‐evoked activity are largely unstudied. Here, a multimodal imaging approach was applied to investigate whether interindividual differences in PCu/PCC fMRI activity, elicited during perceptual discrimination of scene stimuli, were correlated with local brain metabolite levels, measured during resting‐state ¹H‐MRS. Forty healthy young adult participants completed an fMRI perceptual odd‐one‐out task for scenes, objects and faces. ¹H‐MRS metabolites N‐acetyl‐aspartate (tNAA), glutamate (Glx) and γ‐amino‐butyric acid (GABA+) were quantified via PRESS and MEGA‐PRESS scans in a PCu/PCC voxel and an occipital (OCC) control voxel. Whole brain fMRI revealed a cluster in right dorsal PCu/PCC that showed a greater BOLD response to scenes versus faces and objects. When extracted from an independently defined PCu/PCC region of interest, scene activity (vs. faces and objects and also vs. baseline) was positively correlated with PCu/PCC, but not OCC, tNAA. A voxel‐wise regression analysis restricted to the PCu/PCC ¹H‐MRS voxel area identified a significant PCu/PCC cluster, confirming the positive correlation between scene‐related BOLD activity and PCu/PCC tNAA. There were no correlations between PCu/PCC activity and Glx or GABA+ levels. These results demonstrate, for the first time, that scene activity in PCu/PCC is linked to local tNAA levels, identifying a neurochemical influence on interindividual differences in the task‐driven activity of a key brain hub.     

Slow fluctuations in eye position and resting‐state functional magnetic resonance imaging brain activity during visual fixation

The neuronal circuitry that supports voluntary changes in eye position in tasks that require attention‐driven oculo‐motor control is well known. However, less is known about the neuronal basis for eye control during visual fixation. This, together with the fact that visual fixation is one of the most commonly used baseline conditions in resting‐state functional magnetic resonance imaging (fMRI) studies, prompted us to conduct a study in which we employed resting‐state fMRI and concurrent recordings of eye gaze to investigate the relationship between spontaneous changes in eye position during passive visual fixation and intrinsic brain activity. As a control experiment, we recorded fMRI brain activity related to cued voluntary vertical and horizontal changes in eye position in a block‐related task‐evoked fMRI experiment. Our results for the voluntarily performed changes in eye position elicited brain activity in the bilateral occipitotemporal cortex, supplementary motor cortex and frontal eye fields. In contrast, we show that slow fluctuations in eye position during passive visual fixation are linked to intrinsic brain activity, foremost in midline cortical brain regions located in the posteromedial parietal cortex and the medial prefrontal cortex, brain regions that act as core cortical hubs in the brain's default mode network. Our results suggest that subconscious and sustained changes in behavior are tied to intrinsic brain activity on a moment‐by‐moment basis.     

RFRP3 increases food intake in a sex‐dependent manner in the seasonal hamster Phodopus sungorus

In addition to its regulatory role in luteinising hormone secretion, Rfamide‐related peptide 3 (RFRP3) has also been reported to modulate food intake in several mammalian species. Djungarian hamsters (Phodopus sungorus), similar to other seasonal mammals, display a remarkable inhibition of RFRP3 expression in winter short‐day conditions, associated with decreased food intake and bodyweight. This species is therefore a valuable model for assessing whether RFRP3 might be involved in the seasonal control of feeding behaviour and investigating its possible brain targets. We found that, although both male and female animals exhibit the same robust reduction in Rfrp expression in short‐ (SD) compared to long‐day (LD) conditions, acute central administration of RFRP3 displays sex‐dependent effects on food intake. RFRP3 increased food intake in female hamsters in SD or in LD dioestrus, but not in LD pro‐oestrus, indicating that the orexigenic effect of RFRP3 is observed in conditions of low circulating oestradiol levels. In male hamsters, food intake was not changed by acute injections of RFRP3, regardless of whether animals were in SD or LD conditions. Analysing the gene expression of various metabolic neuropeptides in the brain of RFRP3‐injected Djungarian hamsters revealed that Npy expression was increased in female but not in male animals. The present study suggests that, in Djungarian hamsters, RFRP3 exhibits a sex‐dependent orexigenic effect possibly by inducing increased Npy expression.     

The effects of catechol O-methyltransferase genotype on brain activation elicited by affective stimuli and cognitive tasks

Catechol-O-methyltransferase (COMT) degrades the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A functional polymorphism in the COMT gene (val158 met) accounts for a four-fold variation in enzyme activity. The low activity met158 allele has been associated with improved working memory, executive functioning, and attentional control, but also with a higher risk of anxiety-related behaviors. In spite of the strong effect of the COMT genotype on enzyme activity, its effects on behavior are moderate, accounting for only 4% of variance in task performance. Studies of individuals with intermediate phenotypes during activities such as task-dependent brain activation, may more sensitively detect gene effects on the brain. A series of studies using functional magnetic resonance imaging (fMRI) assessed the effects of the COMT val158 met genotype on central processing during working memory, attentional control, and emotional tasks. fMRI revealed a more focused response in the prefrontal cortex (PFC) of met158 allele carriers during a working memory task. A comparable effect during the performance of an attentional control task in the cingulate cortex was also observed. These data indicate that met158 allele load is associated with improved processing efficiency in the PFC and cingulate, which might be due to lower prefrontal dopamine (DA) metabolism, higher DA concentrations, and an increased neuronal signal-to-noise ratio during information processing. During performance of an emotional task, reactivity to unpleasant visual stimuli was positively correlated with the number of met158 alleles in the amygdala, as well as in other limbic and paralimbic nodes. This increased limbic reactivity to unpleasant stimuli might be the underlying cause of the lower emotional resilience against negative mood states observed in individuals with a higher met158 allele load. Thus the met158 allele seems to be beneficial during the performance of working memory and attention-related tasks, whereas the val158 allele appears to be advantageous during the processing of aversive emotional stimuli.     

Intact working memory in non‐manifesting LRRK2 carriers – an fMRI study

Cognitive impairments are prevalent in patients with Parkinson's disease. Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of genetic Parkinsonism. Non‐manifesting carriers of the G2019S mutation in the LRRK2 gene were found to have lower executive functions as measured by the Stroop task. This exploratory study aimed to assess whether the cognitive impairment in non‐manifesting carriers is specific for executive functions or includes other cognitive domains such as working memory. We recruited 77 non‐manifesting first‐degree relatives of Parkinson's disease patients (38 carriers). A block‐design fMRI N‐back task, with 0‐back, 2‐back and 3‐back conditions, was used in order to assess working memory. Participants were well matched on the Montreal Cognitive Assessment, University of Pennsylvania Smell Identification Test, Unified Parkinson's Disease Rating Scale part III, digit span, age, gender and Beck Depression Inventory. The task achieved the overall expected effect in both groups with longer reaction times and lower accuracy rates with increasing task demands. However, no whole‐brain or region‐of‐interest between‐groups differences were found on any of the task conditions. These results indicate that non‐manifesting carriers of the G2019S mutation in the LRRK2 gene have a specific cognitive profile with executive functions, as assessed by the Stroop task, demonstrating significant impairment but with working memory, as assessed with the N‐back task, remaining relatively intact. These finding shed light on the pre‐motor cognitive changes in this unique ‘at risk’ population and should enable more focused cognitive assessments of these cohorts.     

Encoding of global visual motion in the nidopallium caudolaterale of behaving crows

Songbirds possess acute vision. How higher brain centres represent basic and parameterised visual stimuli to process sensory signals according to their behavioural importance has not been studied in a systematic way. We therefore examined how carrion crows (Corvus corone) and their nidopallial visual neurons process global visual motion information in dynamic random‐dot displays during a delayed match‐to‐sample (DMS) task. The behavioural data show that moderately fast motion speeds (16° of visual angle/s) result in superior direction discrimination performance. To characterise how neurons encode and maintain task‐relevant visual motion information, we recorded the single‐unit activity in the telencephalic association area ‘nidopallium caudolaterale’ (NCL) of behaving crows. The NCL is considered to be the avian analogue of the mammalian prefrontal cortex. Almost a third (28%) of randomly selected NCL neurons responded selectively to the motion direction of the sample stimulus, mostly to downward motions. Only few NCL neurons (7.5%) responded consistently to specific motion directions during the delay period. In error trials, when the crows chose the wrong motion direction, the encoding of motion direction was significantly reduced. This indicates that sensory representations of NCL neurons are relevant to the birds’ behaviour. These data suggest that the corvid NCL, even though operating at the apex of the telencephalic processing hierarchy, constitutes a telencephalic site for global motion integration.     

Hemispheric asymmetries in resting‐state EEG and fMRI are related to approach and avoidance behaviour,but not to eating behaviour or BMI

Much of our behaviour is driven by two motivational dimensions—approach and avoidance. These have been related to frontal hemispheric asymmetries in clinical and resting‐state EEG studies: Approach was linked to higher activity of the left relative to the right hemisphere, while avoidance was related to the opposite pattern. Increased approach behaviour, specifically towards unhealthy foods, is also observed in obesity and has been linked to asymmetry in the framework of the right‐brain hypothesis of obesity. Here, we aimed to replicate previous EEG findings of hemispheric asymmetries for self‐reported approach/avoidance behaviour and to relate them to eating behaviour. Further, we assessed whether resting fMRI hemispheric asymmetries can be detected and whether they are related to approach/avoidance, eating behaviour and BMI. We analysed three samples: Sample 1 (n = 117) containing EEG and fMRI data from lean participants, and Samples 2 (n = 89) and 3 (n = 152) containing fMRI data from lean, overweight and obese participants. In Sample 1, approach behaviour in women was related to EEG, but not to fMRI hemispheric asymmetries. In Sample 2, approach/avoidance behaviours were related to fMRI hemispheric asymmetries. Finally, hemispheric asymmetries were not related to either BMI or eating behaviour in any of the samples. Our study partly replicates previous EEG findings regarding hemispheric asymmetries and indicates that this relationship could also be captured using fMRI. Our findings suggest that eating behaviour and obesity are likely to be mediated by mechanisms not directly relating to frontal asymmetries in neuronal activation quantified with EEG and fMRI.     

Expression of the clock gene Rev‐erbα in the brain controls the circadian organisation of food intake and locomotor activity,but not daily variations of energy metabolism

The nuclear receptor REV‐ERBα is part of the molecular clock mechanism and is considered to be involved in a variety of biological processes within metabolically active peripheral tissues as well. To investigate whether Rev‐erbα (also known as Nr1d1) in the brain plays a role in the daily variations of energy metabolism, feeding behaviour and the sleep‐wake cycle, we studied mice with global (GKO) or brain (BKO) deletion of Rev‐erbα. Mice were studied both in a light/dark cycle and in constant darkness, and then 24‐hour variations of Respiratory quotient (RQ) and energy expenditure, as well as the temporal patterns of rest‐activity and feeding behaviour, were recorded. The RQ increase of GKO mice was not detected in BKO animals, indicating a peripheral origin for this metabolic alteration. Arrhythmic patterns of locomotor activity were only found in BKO mice. By contrast, the circadian rhythm of food intake was lost both in GKO and BKO mice, mostly by increasing the number of daytime meals. These changes in the circadian pattern of feeding behaviour were, to some extent, correlated with a loss of rhythmicity of hypothalamic Hcrt (also named Orx) mRNA levels. Taken together, these findings highlight that Rev‐erbα in the brain is involved in the temporal partitioning of feeding and sleep, whereas its effects on energy metabolism are mainly exerted through its peripheral expression.     

Unaltered Hypothalamic Metabolic Gene Expression in Kiss1r Knockout Mice Despite Obesity and Reduced Energy Expenditure

Kisspeptin controls reproduction by stimulating gonadotrophin‐releasing hormone neurones via its receptor Kiss1r. Kiss1r is also expressed other brain areas and in peripheral tissues, suggesting additional nonreproductive roles. We recently determined that Kiss1r knockout (KO) mice develop an obese and diabetic phenotype. In the present study, we investigated whether Kiss1r KOs develop this metabolic phenotype as a result of alterations in the expression of metabolic genes involved in the appetite regulating system of the hypothalamus, including neuropeptide Y (Npy) and pro‐opiomelanocortin (Pomc), as well as leptin receptor (Lepr), ghrelin receptor (Ghsr), and melanocortin receptors 3 and 4 (Mc3r, Mc4r). Body weights, leptin levels and hypothalamic gene expression were measured in both gonad‐intact and gonadectomised (GNX) mice at 8 and 20 weeks of age that had received either normal chow or a high‐fat diet. We detected significant increases in Pomc expression in gonad‐intact Kiss1r KO mice at 8 and 20 weeks, although there were no alterations in the other metabolic‐related genes. However, the Pomc increases appeared to reflect genotype differences in circulating sex steroids, because GNX wild‐type and Kiss1r KO mice exhibited similar Pomc levels, along with similar Npy levels. The altered Pomc gene expression in gonad‐intact Kiss1r KO mice is consistent with previous reports of reduced food intake in these mice and may serve to increase the anorexigenic drive, perhaps compensating for the obese state. However, the surprising overall lack of changes in any of the hypothalamic metabolic genes in GNX KO mice suggests that the aetiology of obesity in the absence of kisspeptin signalling may reflect peripheral rather than central metabolic impairments.     

5‐HTTLPR moderates the association between interdependence and brain responses to mortality threats

While behavioral research suggests an association between cultural worldview and decreased anxiety of death, the underlying neurobiological mechanisms remain unclear. Using functional MRI, we investigated whether and how the serotonin transporter promoter polymorphism (5‐HTTLPR), which has been associated with mental disorders such as anxiety and depression, moderates the associations between a cultural trait (i.e., interdependence) and self‐report of death anxiety/depression and between interdependence and brain responses to mortality threats. Long/long and short/short allele carriers of the 5‐HTTLPR were scanned using fMRI while they performed a one‐back task on death‐related, death‐unrelated negative, and neutral words. Participants’ interdependence and death anxiety/depression were assessed using questionnaires after scanning. We found that participants who assessed themselves with greater interdependence reported lower death anxiety/depression and showed decreased neural response to death‐related words in emotion‐related brain regions including the anterior cingulate, putamen, and thalamus. However, these results were evident in long/long allele carriers of the 5‐HTTLPR but not in short/short allele carriers who even showed positive associations between interdependence and neural activities in the anterior cingulate, putamen and thalamus in response to death‐related words. Our findings suggest candidate mechanisms for explaining the complex relationship between genotype, cultural traits, and mental/neural responses to mortality threats. Hum Brain Mapp 38:6157–6171, 2017. © 2017 Wiley Periodicals, Inc.     

Effects of SCN1A and GABA Receptor Genetic Polymorphisms on Carbamazepine Tolerability and Efficacy in Chinese Patients with Partial Seizures: 2‐Year Longitudinal Clinical Follow‐Up

Aims: To investigate the tolerability and efficacy of carbamazepine treatment in patients with partial‐onset seizures and the association with polymorphisms in the sodium channel α‐subunit type 1 (SCN1A), and gamma‐aminobutyric acid (GABA) receptor genes among the Chinese Han population. Methods: 448 patients were genotyped for single nucleotide polymorphisms selected of the SCN1A and GABA‐receptor genes. Monotherapy with carbamazepine (CBZ) was administered to the patients. The effectiveness of CBZ treatment was evaluated with regard to efficacy by the decrease in seizures and tolerability by retention rates. Results: SCN1A rs3812718 A/G with CBZ tolerability (P= 0.038) throughout 24 months of clinical follow‐up and the GABRA1 rs2290732 A/G were significantly associated with CBZ tolerability (P= 0.001). The maintenance dose and serum level of CBZ in AA genotype carriers of rs3812718 A/G were significantly higher than those of GG genotype carriers between 3 and 12 months of follow‐up. The proportion of AA genotype carriers of rs2298771 A/G with seizure free was significantly higher than that of AG+GG genotype carriers from 3 months to 15 months of follow‐up (P < 0.05). Conclusion: rs3812718 A/G and rs2290732 A/G polymorphisms affected the tolerability of CBZ. rs2298771 A/G was associated with efficacy of CBZ treatment.     

A resting‐state fMRI study of obese females between pre‐ and postprandial states before and after bariatric surgery

Past studies utilizing resting‐state functional MRI (rsfMRI), have shown that obese humans exhibit altered activity in brain areas related to reward compared to normal‐weight controls. However, to what extent bariatric surgery‐induced weight loss alters resting‐state brain activity in obese humans is less well‐studied. Thus, we measured the fractional amplitude of low‐frequency fluctuations from eyes‐closed, rsfMRI in obese females (n = 11, mean age = 42 years, mean BMI = 41 kg/m²) in both a pre‐ and postprandial state at two time points: four weeks before, and four weeks after bariatric surgery. Several brain areas showed altered resting‐state activity following bariatric surgery, including the putamen, insula, cingulate, thalamus and frontal regions. Activity augmented by surgery was also dependent on prandial state. For example, in the fasted state, activity in the middle frontal and pre‐ and postcentral gyri was found to be decreased after surgery. In the sated state, activity within the insula was increased before, but not after surgery. Collectively, our results suggest that resting‐state neural functions are rapidly affected following bariatric surgery and the associated weight loss and change in diet.     

Emotional fronto‐cingulate cortex activation and brain derived neurotrophic factor polymorphism in premenstrual dysphoric disorder

Premenstrual dysphoric disorder (PMDD) is the prototypical sex‐specific disorder in which symptom onset and offset require a particular hormonal milieu and for which there is moderate heritability. The present study investigated brain emotion processing in PMDD and healthy controls, as well as functional polymorphisms in two candidate genes for PMDD, the serotonin transporter (5‐HTT) and brain derived neurotrophic factor (BDNF). The 5‐HTT linked polymorphic region (5‐HTTLPR) and BDNF Val66Met polymorphisms were genotyped in 31 patients with PMDD and 31 healthy controls. A subset of 16 patients and 15 controls participated in two functional magnetic resonance imaging‐sessions performing an emotion processing task; once in the mid‐follicular, and once in the late luteal phase which corresponds with maximum severity of mood symptoms. Genotypes were not directly associated with PMDD. A main effect of group was found in the whole brain analysis, with patients having lower activation of the pre‐genual anterior cingulate and ventro‐medial prefrontal cortex, independent of menstrual cycle phase. Post‐hoc functional ROI analyses in the fronto‐cingulate cluster showed no effect of 5‐HTTLPR genotype but a genotype‐by‐group‐by‐phase interaction effect of BDNF Val66Met. Women with PMDD who were carriers of the Met‐allele had lower fronto‐cingulate cortex activation in the luteal phase compared to Met‐allele carrying controls. The results provide suggestive evidence of impaired emotion‐induced fronto‐cingulate cortex activation in PMDD patients. Although limited by a small sample, the potential influence of BDNF Val66Met in PMDD is in line with preclinical findings. Hum Brain Mapp 35:4450–4458, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.