Recapitulation of the association of the Val66Met polymorphism of BDNF gene with BMI in Koreans

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) regulates food intake and the control of body weight. A common polymorphism in human BDNF, Val66Met (single-nucleotide polymorphism database (dbSNP) no. rs6265), impairs intracellular trafficking, resulting in the reduced secretion of BDNF. Several European studies have indicated that Val66Met is associated with BMI. In this study, we examined the association of the Val66Met polymorphism with BMI in Koreans (n = 20,270) from three independent epidemiological cohorts. All three studies observed a consistent association of this polymorphism with BMI, and their combined analysis demonstrated a robust correlation (β = -0.17 ± 0.03 and P = 5.6 × 10(-8)). We also examined the effect of smoking on the link between Val66Met and BMI. The association of Val66Met with BMI was statistically significant only in the smoking group, reflecting a possible interaction between smoking and the BDNF polymorphism for BMI. Thus, we have confirmed BDNF as a genetic risk factor for BMI in an Asian population and hypothesize that the Val66Met mutation influences individual differences in BMI. In addition, smoking might interact with BDNF Val66Met to modulate BMI.     

Modulating effect of Val66Met polymorphism of brain-derived neurotrophic factor gene on clinical and psychological characteristics of patients with schizophrenia

The brain-derived neurotrophic factor (BDNF) gene is an important candidate gene for schizophrenia. The association of BDNF with schizophrenia has been extensively analyzed using the polymorphism Val66Met. There is accumulating evidence that Val66Met is associated with clinical presentations of schizophrenia rather than with the disease itself. In this study, BDNF allele and genotype distributions were compared in patients (n = 1785) and healthy controls (n = 1092). There was no association between the Val66Met polymorphism and schizophrenia. The marker was not associated with the presence of the affective syndrome either. At the same time, the ValVal genotype was associated with higher anxiety levels in male patients as assessed with PANSS. Patients’ personality traits were characterized using the personality inventories EPI, MMPI, and STAI (n = 363), and their cognitive functions, attention (n = 282) and verbal fluency (n = 392), were evaluated. Patients with the ValVal genotype showed higher levels of anxiety (by MMPI) and better performance on neurocognitive tests. The genotype and trait anxiety (by STAI score) had an interaction effect on cognitive functions. In patients with higher anxiety, performance on cognitive tests did not depend on the genotype, while in patients with lower levels of anxiety, the ValVal genotype was associated with significantly better performance. This effect should be taken into account when studying associations of the Val66Met polymorphism with cognitive functions in patients with schizophrenia.     

Association between the Val66Met polymorphism of brain-derived neurotrophic factor gene and schizophrenia in Russians

Recent studies have demonstrated a role of the brain-derived neurotrophic factor (BDNF) in schizophrenia. An association between the Val66Met BDNF polymorphism has been reported but the results of different studies are inconsistent. An aim of the present article is to study the allele and genotype distribution in patients with schizophrenia (783) and mentally healthy controls (633). No statistically significant between-group differences have been found. When the group of patients has been stratified by sex and form of schizophrenia, the higher frequency of the Val/Val genotype is observed in the subgroup of men with continuous (chronic) schizophrenia as compared to men with attack-like form (p = 0.047). Clinical symptoms assessed with the PANSS were more severe in male patients with the Val/Val genotype. The Val66Met polymorphism was not associated with forms of schizophrenia or clinical symptoms in female patients. The results obtained suggest that the association between the BDNF gene and schizophrenia may be related to sex and clinical heterogeneity of disease. The Val/Val genotype is associated with severer form of schizophrenia in men.     

Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls

Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype?×?diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level?×?genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism.     

BDNF variant linked to anxiety-related behaviors

Brain-derived neurotrophic factor (BDNF) is the most-abundant neurotrophin in the brain. In mammals, it is synthesized as a precursor called proBDNF, which is proteolytically cleaved to generate mature BDNF. The BDNF gene is located on chromosome 11p13, and a functional single nucleotide polymorphism (SNP) of this gene has been shown to produce a valine (Val)-to-methionine (Met) substitution in the proBDNF protein at codon 66 (Val66Met). Several papers suggest that this SNP is related to decreased hippocampal volume and hippocampus-mediated memory performance in humans. Recently, Chen et al. generated a variant BDNF mouse (BDNF(Met/Met)) that reproduces the phenotypic hallmarks in humans with a variant Met allele. In the behavioral analysis, BDNF(Met/Met) mice show increased anxiety-related behaviors. This mini-review examines the impact of Met substitution of proBDNF on anxiety-related behaviors.     

Association of the Val66Met polymorphism of the brain-derived neurotrophic factor gene with schizophrenia in Russians

According to recent data, the brain-derived neurotrophic factor (BDNF) is involved in schizophrenia. An association of the Val66Met polymorphism of the BDNF gene has been reported, but the results of different studies are discrepant. The allele and genotype frequency distributions of BDNF were studied in 783 schizophrenics and 633 mentally healthy controls. Significant between-group differences were not detected. When the patients were stratified by sex and schizophrenia form, men with continuous (chronic) schizophrenia were found to have a significantly higher frequency of the Val/Val genotype as compared to men with the episodic form (P = 0.047). Clinical symptoms assessed by the PANSS in men with the Val/Val genotype were more severe than in men with the Met/Met genotype (P = 0.044). No difference in BDNF genotype frequency distribution was observed between female groups differing in disease form or the severity of clinical symptoms. It was concluded that the association of the Val66Met polymorphism with schizophrenia is affected by the sex of patients and clinical heterogeneity of the disease and that the Val/Val genotype is associated with more severe schizophrenia in males.     

Association of Brain-Derived Neurotrophic Factor Gene Val66Met Polymorphism with Primary Dysmenorrhea

Primary dysmenorrhea (PDM), the most prevalent menstrual cycle-related problem in women of reproductive age, is associated with negative moods. Whether the menstrual pain and negative moods have a genetic basis remains unknown. Brain-derived neurotrophic factor (BDNF) plays a key role in the production of central sensitization and contributes to chronic pain conditions. BDNF has also been implicated in stress-related mood disorders. We screened and genotyped the BDNF Val66Met polymorphism (rs6265) in 99 Taiwanese (Asian) PDMs (20–30 years old) and 101 age-matched healthy female controls. We found that there was a significantly higher frequency of the Met allele of the BDNF Val66Met polymorphism in the PDM group. Furthermore, BDNF Met/Met homozygosity had a significantly stronger association with PDM compared with Val carrier status. Subsequent behavioral/hormonal assessments of sub-groups (PDMs = 78, controls = 81; eligible for longitudinal multimodal neuroimaging battery studies) revealed that the BDNF Met/Met homozygous PDMs exhibited a higher menstrual pain score (sensory dimension) and a more anxious mood than the Val carrier PDMs during the menstrual phase. Although preliminary, our study suggests that the BDNF Val66Met polymorphism is associated with PDM in Taiwanese (Asian) people, and BDNF Met/Met homozygosity may be associated with an increased risk of PDM. Our data also suggest the BDNF Val66Met polymorphism as a possible regulator of menstrual pain and pain-related emotions in PDM. Absence of thermal hypersensitivity may connote an ethnic attribution. The presentation of our findings calls for further genetic and neuroscientific investigations of PDM.     

Genetic variation in brain-derived neurotrophic factor and human fear conditioning

Brain-derived neurotrophic factor (BDNF) has been implicated in hippocampal-dependent learning processes, and carriers of the Met allele of the Val66Met BDNF genotype are characterized by reduced hippocampal structure and function. Recent nonhuman animal work suggests that BDNF is also crucial for amygdala-dependent associative learning. The present study sought to examine fear conditioning as a function of the BDNF polymorphism. Fifty-seven participants were genotyped for the BDNF polymorphism and took part in a differential-conditioning paradigm. Participants were shocked following a particular conditioned stimulus (CS+) and were also presented with stimuli that ranged in perceptual similarity to the CS+ (20, 40 or 60% smaller or larger than the CS+). The eye blink component of the startle response was measured to quantify fear conditioning; post-task shock likelihood ratings for each stimulus were also obtained. All participants reported that shock likelihood varied with perceptual similarity to the CS+ and showed potentiated startle in response to CS ± 20% stimuli. However, only the Val/Val group had potentiated startle responses to the CS+. Met allele carrying individuals were characterized by deficient fear conditioning – evidenced by an attenuated startle response to CS+ stimuli. Variation in the BDNF genotype appears related to abnormal fear conditioning, consistent with nonhuman animal work on the importance of BDNF in amygdala-dependent associative learning. The relation between genetic variation in BDNF and amygdala-dependent associative learning deficits is discussed in terms of potential mechanisms of risk for psychopathology.     

Interaction of Motor Training and Intermittent Theta Burst Stimulation in Modulating Motor Cortical Plasticity: Influence of BDNF Val66Met Polymorphism

Cortical physiology in human motor cortex is influenced by behavioral motor training (MT) as well as repetitive transcranial magnetic stimulation protocol such as intermittent theta burst stimulation (iTBS). This study aimed to test whether MT and iTBS can interact with each other to produce additive changes in motor cortical physiology. We hypothesized that potential interaction between MT and iTBS would be dependent on BDNF Val66Met polymorphism, which is known to affect neuroplasticity in the human motor cortex. Eighty two healthy volunteers were genotyped for BDNF polymorphism. Thirty subjects were assigned for MT alone, 23 for iTBS alone, and 29 for MT + iTBS paradigms. TMS indices for cortical excitability and motor map areas were measured prior to and after each paradigm. MT alone significantly increased the motor cortical excitability and expanded the motor map areas. The iTBS alone paradigm also enhanced excitability and increased the motor map areas to a slightly greater extent than MT alone. A combination of MT and iTBS resulted in the largest increases in the cortical excitability, and the representational motor map expansion of MT + iTBS was significantly greater than MT or iTBS alone only in Val/Val genotype. As a result, the additive interaction between MT and iTBS was highly dependent on BDNF Val66Met polymorphism. Our results may have clinical relevance in designing rehabilitative strategies that combine therapeutic cortical stimulation and physical exercise for patients with motor disabilities.     

No effect of 5HTTLPR or BDNF Val66Met polymorphism on hippocampal morphology in major depression

Neuroimaging research implicates the hippocampus in the aetiology of major depressive disorder (MDD). Imaging genetics studies have investigated the influence of the serotonin transporter-linked polymorphic region (5HTTLPR) and brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on the hippocampus in healthy individuals and patients with depression (MDD). However, conflicting results have led to inconclusive evidence about the effect of 5HTTLPR or BDNF on hippocampal volume (HCV). We hypothesized that analysis methods based on three-dimensional (3D) hippocampal shape mapping could offer improved sensitivity to clarify these effects. Magnetic resonance imaging data were collected in parallel samples of 111 healthy individuals and 84 MDD patients. Manual hippocampal segmentation was conducted and the resulting data used to investigate the influence of 5HTTLPR and BDNF Val66Met genotypes on HCV and 3D shape within each sample. Hippocampal volume normalized by intracranial volume (ICV) showed no significant difference between 5HTTLPR S allele carriers and L/L homozygotes or between BDNF Met allele carriers and Val/Val homozygotes in the group of healthy individuals. Moreover, there was no significant difference in normalized HCV between 5HTTLPR diallelic and triallelic classifications or between the BDNF Val66Met genotypes in MDD patients, although there was a relationship between BDNF Val66Met and ICV. Shape analysis detected dispersed between-group differences, but these effects did not survive multiple testing correction. In this study, there was no evidence of a genetic effect for 5HTTLPR or BDNF Val66Met on hippocampal morphology in either healthy individuals or MDD patients despite the relatively large sample sizes and sensitive methodology.     

5-HTTLPR and BDNF Val66Met polymorphisms moderate effects of stress on rumination

This study examined whether polymorphisms in the serotonin transporter (SLC6A4, 5-HTTLPR) and brain-derived neurotropic factor (BDNF Val66Met, rs6265) genes moderate the relationship between life stress and rumination. Participants were a large homogenous group of healthy, unmedicated, never depressed individuals with few current symptoms of depression (N = 273). Results indicate that individuals with two short (S) alleles of the 5-HTTLPR polymorphism or two Met alleles of the BDNF Val66Met polymorphism ruminate more under conditions of life stress, compared to the other genotypes. Moreover, the accumulation of risk alleles (i.e. S and Met alleles) across genes is associated with significantly greater rumination in the context of life stress. These results suggest that both 5-HTTLPR and BDNF Val66Met moderate the relationship between life stress and rumination. These findings support the notion that variation in these genes is associated with biological sensitivity to the negative effects of stress.     

A preliminary study suggests that nicotine and prefrontal dopamine affect cortico‐striatal areas in smokers with performance feedback

Nicotine and tonic dopamine (DA) levels [as inferred by catechol‐O‐methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico‐striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy .     

Interaction between BDNF Val66Met and childhood trauma on adult's violent suicide attempt

Genetic factors, specially those related to serotoninergic activities, and childhood maltreatment have both been implicated in suicidal behaviour (SB). However, little attention has been paid to the possible interaction between genes and childhood maltreatment in the comprehension of SB. Brain-derived neurotrophic factor (BDNF) plays an important role in the growth of serotoninergic neurons during childhood and therefore is a good candidate for studies on SB. Moreover, decreased levels of BDNF have been found in the prefrontal cortex of suicide victims. In our study we wanted to see if Val66Met (a BDNF functional single-nucleotide polymorphism) could moderate the effect of childhood maltreatment on the onset, number and violence of SB in a sample of 813 Caucasian suicide attempters. Childhood maltreatment was evaluated using the Childhood Trauma Questionnaire. We used a regression framework to test the interaction between Val66Met and childhood maltreatment. Childhood sexual abuse was associated with violent suicide attempts (SA) in adulthood only among Val/Val individuals and not among Val/Met or Met/Met individuals ( P  = 0.05). The severity of childhood maltreatment was significantly associated with a higher number of SA and with a younger age at onset of suicide attempt. This result suggests that Val66Met modulates the effect of childhood sexual abuse on the violence of SB. It is proposed that childhood sexual abuse elicits brain structural modifications through BDNF dysfunction and enhances the risk of violent SB in adulthood.     

Genetic variation on the BDNF gene is not associated with differences in white matter tracts in healthy humans measured by tract‐based spatial statistics

The brain‐derived neurotrophic factor (BDNF) is a member of the neurotrophin family and involved in nerve growth and survival. It has also become a major research focus in the investigation of both cognitive and affective processes in the human brain in the last years. Especially, a single nucleotide polymorphism on the BDNF gene called BDNF Val66Met gained a lot of attention, because of its effect on activity‐dependent BDNF secretion and its link to negative emotionality and impaired memory processes. A well‐replicated finding from genetic structural imaging showed that carriers of the less frequent 66Met allele show diminished gray matter volume in several areas of the temporal lobe. New imaging techniques like diffusion tensor imaging now allow investigating the influence of BDNF Val66Met on white matter integrity. We applied tract‐based spatial statistics in a brain image dataset including n = 99 healthy participants. No significant differences between the 66Met and homozygous 66Val carriers were observed when correcting for multiple comparisons. In summary, the BDNF Val66Met polymorphism seems not to play a substantial role with respect to the modulation of the white matter integrity in healthy subjects. Although not in the focus of this study, we also investigated the influence of Eysenck's Personality Questionnaire on the white matter tracts. No significant results could be observed.     

Identification of BDNF Sensitive Electrophysiological Markers of Synaptic Activity and Their Structural Correlates in Healthy Subjects Using a Genetic Approach Utilizing the Functional BDNF Val66Met Polymorphism

Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.     

Brain Activation in Motor Sequence Learning Is Related to the Level of Native Cortical Excitability

Cortical excitability may be subject to changes through training and learning. Motor training can increase cortical excitability in motor cortex, and facilitation of motor cortical excitability has been shown to be positively correlated with improvements in performance in simple motor tasks. Thus cortical excitability may tentatively be considered as a marker of learning and use-dependent plasticity. Previous studies focused on changes in cortical excitability brought about by learning processes, however, the relation between native levels of cortical excitability on the one hand and brain activation and behavioral parameters on the other is as yet unknown. In the present study we investigated the role of differential native motor cortical excitability for learning a motor sequencing task with regard to post-training changes in excitability, behavioral performance and involvement of brain regions. Our motor task required our participants to reproduce and improvise over a pre-learned motor sequence. Over both task conditions, participants with low cortical excitability (CElo) showed significantly higher BOLD activation in task-relevant brain regions than participants with high cortical excitability (CEhi). In contrast, CElo and CEhi groups did not exhibit differences in percentage of correct responses and improvisation level. Moreover, cortical excitability did not change significantly after learning and training in either group, with the exception of a significant decrease in facilitatory excitability in the CEhi group. The present data suggest that the native, unmanipulated level of cortical excitability is related to brain activation intensity, but not to performance quality. The higher BOLD mean signal intensity during the motor task might reflect a compensatory mechanism in CElo participants.     

The brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of parental rearing on personality traits in healthy subjects

There is a growing body of data suggesting that gene-environment interaction is critical in the characterization of personality traits; however, previous studies have not taken into consideration variability in parental rearing as an environmental factor. In this study, we examined the effects of the interaction between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on personality traits in 710 healthy Japanese subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. Assessment of personality traits was performed by the temperament and character inventory (TCI), which has seven dimensions, i.e. novelty seeking, harm avoidance, reward dependence, persistence, self-directedness, cooperativeness and self-transcendence. Parental rearing has significant main effects on some TCI dimensions, but no significant main effects of the BDNF genotype on the TCI scores were found. The interaction between the BDNF genotype and maternal care of the PBI had significant effects on harm avoidance and self-directedness of the TCI. Post hoc analyses showed that decreased maternal care was correlated with increased harm avoidance and decreased self-directedness, and for both personality traits the partial correlation coefficient was highest in the Met/Met genotype group and lowest in the Val/Val genotype group and the value of the Val/Met genotype group was in the middle. Data from this study suggest that the BDNF Val66Met polymorphism modulates the effects of parental rearing, especially maternal care, on harm avoidance and self-directedness in healthy subjects.     

BDNF Val66Met Variant and Smoking in a Chinese Population

Several recent studies have supported the hypothesis that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, might be associated with nicotine addiction. Association studies have also suggested that the BDNF gene might play a role in the susceptibility to nicotine dependence but results appear contradictory. The present work was therefore undertaken to examine the association of smoking with the BDNF Val66Met gene polymorphism in Chinese population. The BDNF Val66Met gene polymorphism was examined in 628 healthy male volunteers including 322 smokers and 306 non-smokers. Also, the BDNF serum levels were measured in 136 smokers and 97 nonsmokers. Our results showed no significant association between the BDNF Val66Met polymorphism or serum levels among smokers and non-smokers. Smokers with the Met allele however started smoking significantly earlier than those with the Val/Val genotype (mean age at smoking initiation of 17.4, 17.9 and 21.2 years for Met/Met, Met/Val, and Val/Val, respectively; both p<0.05). No other significant differences between other variables such as number of cigarettes per day, smoking severity as measured by the Fagerstrom Test for Nicotine Dependence (FTND) score and carbon monoxide (CO) levels (all p>0.05). In addition, there was no main effect of genotype on serum BDNF levels. Our findings suggest that the BDNF Val66Met polymorphism may not be involved in susceptibility to smoking among the Chinese male population, but may influence the age at which smoking is initiated. However, the findings must be interpreted with caution because of the relatively small sample size for an association study. Results should be confirmed in a larger cohort.     

Effects of the BDNF Val66Met Polymorphism and Met Allele Load on Declarative Memory Related Neural Networks

It has been suggested that the BDNF Val66Met polymorphism modulates episodic memory performance via effects on hippocampal neural circuitry. However, fMRI studies have yielded inconsistent results in this respect. Moreover, very few studies have examined the effect of met allele load on activation of memory circuitry. In the present study, we carried out a comprehensive analysis of the effects of the BDNF polymorphism on brain responses during episodic memory encoding and retrieval, including an investigation of the effect of met allele load on memory related activation in the medial temporal lobe. In contrast to previous studies, we found no evidence for an effect of BDNF genotype or met load during episodic memory encoding. Met allele carriers showed increased activation during successful retrieval in right hippocampus but this was contrast-specific and unaffected by met allele load. These results suggest that the BDNF Val66Met polymorphism does not, as previously claimed, exert an observable effect on neural systems underlying encoding of new information into episodic memory but may exert a subtle effect on the efficiency with which such information can be retrieved.