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BDNF Val66Met polymorphism and goal-directed behavior in healthy elderly — evidence from auditory distraction
... Исследования событийно-связанных потенциалов мозга показали, что носители аллеля Met имеют худшие электрофизиологические показатели внимания, по сравнению с носителями Val, что проявляется в увеличении латентного периода и в уменьшении амплитуды компонента Р300 Getzmann, 2013), в то же время в другой работе не было выявлено специфических различий в фоновой ЭЭГ и в параметрах P300 у носителей аллеля Met . ...
... С использованием слуховых событийно-связанных потенциалов (ERP) получены данные о влиянии полиморфизма BDNF Val66Met на когнитивные процессы, составляющие цикл отвлечения внимания, ориентации и переориентации внимания. При этом установлено, что в условиях отвлечения внимания с помощью слуховых дистракторов, эффективность носителей генотипа Val/Val меньше, чем у носителей гетерозиготного генотипа Val/Met (Getzmann et al., 2013). ...
The article presents the results of the study of induced brain activity in carriers of polymorphic variants of the gene of the brain neurotrophic factor BDNF and the gene of the receptor serotonin HTR2A, obtained in the evaluation of stimulatory images of emotionogenic character. The image database used in the work included 573 images assigned to three groups: neutral, positive, negative. 40 people of both sexes aged 19—22 years were examined. The isolation of DNA from the buccal epithelium cells was carried out by PCR (OOO «BiReT», Moscow, Russia). During the genetic analysis, the following DNA sections were analyzed: Neurotrophic factor of the brain BDNF, Serotonin receptor HTR2A. To register the electroencephalogram and evoked potentials (EP) of the brain, a multichannel electroencephalograph Neurovisor-136 (manufactured by ISS, Russia) was used. The recording was carried out unipolarly according to the «5—5» scheme in 128 leads. As a result of the study, it was found that in persons with a heterozygous Val / Met genotype of the cerebral neurotrophic factor BDNF, a more pronounced emotional response to both positive and negative stimuli was observed. For persons with a homozygous Val / Val genotype, a more detailed treatment of the details of the visual image is characteristic. For persons with a dominant homozygous G / G genotype of the HTR2A serotonin receptor gene, weighted decision-making in stimulus analysis is characteristic. In individuals with recessive homozygous genotype A / A HTR2A, evaluating the visual stimulus as negative requires the use of significantly larger brain resources, compared to the carriers of the dominant allele G.
... Moreover, Erickson et al. [17] showed that Val/Val carriers aged 65 outperformed Met carriers of the same age on an executive functioning task, whereas contradictory results were observed at an average age of 75. Similarly, recent evidence suggests that the functions of the fronto-striatal circuits are more efficient in elderly BDNF Met-allele carriers than in individuals who are homozygous for Val [17][18][19][20][21]. Cognitive processes assessed using event-related potentials (ERPs) seem to vary according to the isoform of the gene [21,22]. Taken together, these results suggest that the BDNF Val66Met polymorphism differently affects various cognitive processes. ...
... These results appear to contradict our results and other results obtained in several studies assessing the relationship between cognition and BDNF Val66Met [14,15]. However, Getzmann et al. [22] consider that the effect of BDNF polymorphism may differ depending on the brain areas supporting the different cognitive functions. Future studies should more precisely examine the cognitive functions that are negatively affected by specific iso-forms of the BDNF Val66Met polymorphism using more selective cognitive evaluations; i.e., a large battery of two or three cognitive tests per cognitive function that declines with age, mainly the speed of information processing, episodic memory and executive functions. ...
Physical Activity and Cognitive Aging: Modulatory Effects of the Brain-Derived Neurotrophic Factor Gene
Old age is generally associated with functional and structural changes in the central nervous system (CSN). Among all the strategies used to maintain the autonomy of the elderly, practicing regular physical activity seems to be an effective way of slowing down the deleterious effects of brain aging, in particular by improving the efficacy of neuroplasticity mechanisms. According to this neurotrophic hypothesis, several neurotrophins released during exercise, including the brain-derived neurotrophic factor (BDNF), contribute to preserving the integrity of the CSN during the aging process. However, secretion of these neurotrophins is also controlled by genes. For example, one of the variations of the gene regulating the secretion of BDNF leads to reduced cerebral secretion of the protein and to poorer cognitive performance. The main objective of this review is to assess the studies that show the moderating effect of the BDNF gene on cognitive performance. The second objective is to explain the importance of a genetic approach in understanding the mechanisms underlying the relationship between physical activity and cognition. Finally, the paper puts forward some future research avenues based on an interdisciplinary approach, combining genetics, cognitive neuroscience, exercise psychology, and human physiology.
... The rs6265 variant has been reported to affect the regulated secretion, neural activation, and neuroplastic effect of BDNF as well as neurocognitive functions in humans [29,[66][67]. It has been associated with memory and learning [29,[68][69][70][71][72][73][74] and as well as with aspects of executive functioning [66,[75][76][77][78][79][80], including response inhibition [75], decision making [77][78], task-switching [79], attention shifting and sequencing [80]. Meanwhile, the BDNF-LCPR variants on the other hand have been associated with an increased risk for bipolar disorder [81]. ...
... The rs6265 variant has been reported to affect the regulated secretion, neural activation, and neuroplastic effect of BDNF as well as neurocognitive functions in humans [29,[66][67]. It has been associated with memory and learning [29,[68][69][70][71][72][73][74] and as well as with aspects of executive functioning [66,[75][76][77][78][79][80], including response inhibition [75], decision making [77][78], task-switching [79], attention shifting and sequencing [80]. Meanwhile, the BDNF-LCPR variants on the other hand have been associated with an increased risk for bipolar disorder [81]. ...
The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery.. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen’s d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1= baseline/ admission vs. T2= 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M= -11.44, SD= 10.0, p= .01, d= 1.22), executive function (M= -11.56, SD= 11.7, p= .02, d= 1.05) and overall performance (M= -6.89 SD= 5.3, p= .00, d= 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M=-11.0, SD= 13.1, p= .00, d= .86) and overall cognitive performance (M= -5.25, SD= 8.1, p = .01, d= .66) .The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.
... decreased d frequency band total power and synchronization during an error related negativity (ERN) task) [49] and attention (i.e. P300 latency increase and amplitude reduction) [29,50]. ...
... As part of a larger investigation into the role of BDNF on synaptic and neural network activity in humans, we focused our investigation on electrophysiological markers including ERN, Mismatch Negativity (MMN), resting EEG activity/synchronization and P300. These EEG/ERP markers were selected because they have been shown to be sensitive to the BDNF Val66Met polymorphism [29,49,50], and/or impaired in neurodegenerative disorders including AD (e.g. [51,52]). ...
... Moreover, Erickson et al. [17] showed that Val/Val carriers aged 65 outperformed Met carriers of the same age on an executive functioning task, whereas contradictory results were observed at an average age of 75. Similarly, recent evidence suggests that the functions of the fronto-striatal circuits are more efficient in elderly BDNF Met-allele carriers than in individuals who are homozygous for Val [17][18][19][20][21]. Cognitive processes assessed using event-related potentials (ERPs) seem to vary according to the isoform of the gene [21,22]. Taken together, these results suggest that the BDNF Val66Met polymorphism differently affects various cognitive processes. ...
... These results appear to contradict our results and other results obtained in several studies assessing the relationship between cognition and BDNF Val66Met [14,15]. However, Getzmann et al. [22] consider that the effect of BDNF polymorphism may differ depending on the brain areas supporting the different cognitive functions. Future studies should more precisely examine the cognitive functions that are negatively affected by specific iso-forms of the BDNF Val66Met polymorphism using more selective cognitive evaluations; i.e., a large battery of two or three cognitive tests per cognitive function that declines with age, mainly the speed of information processing, episodic memory and executive functions. ...
Background: The brain-derived neurotrophic factor (BDNF) concentration is highest in the hippocampus compared with that in other brain structures and affects episodic memory, a cognitive function that is impaired in older adults. According to the neurotrophic hypothesis, BDNF released during physical activity enhances brain plasticity and consequently brain health. However, even if the physical activity level is involved in the secretion of neurotrophin, this protein is also under the control of a specific gene. The aim of the present study was to examine the effect of the interaction between physical activity and BDNF Val66Met (rs6265), a genetic polymorphism, on episodic memory.
Methods: Two hundred and five volunteers aged 55 and older with a Mini Mental State Examination score ≥ 24 participated in this study. Four groups of participants were established according to their physical activity level and polymorphism BDNF profile (Active Val homozygous, Inactive Val homozygous, Active Met carriers, Inactive Met carriers). Episodic memory was evaluated based on the delayed recall of the Logical Memory test of the MEM III battery.
Results: As expected, the physical activity level interacted with BDNF polymorphism to affect episodic memory performance (p < .05). The active Val homozygous participants significantly outperformed the active Met carriers and inactive Val homozygous participants.
Conclusion: This study clearly demonstrates an interaction between physical activity and BDNF Val66Met polymorphism that affects episodic memory in the elderly and confirms that physical activity contributes to the neurotrophic mechanism implicated in cognitive health. The interaction shows that only participants with Val/Val polymorphism benefited from physical activity.
... Compared to Val/Val subjects, Met carriers show poorer performance in hippocampal-dependent memory tasks Hariri et al., 2003;Schofield et al., 2009) and reduced hippocampal gray matter volume (Pezawas et al., 2004;Bueller et al., 2006;Frodl et al., 2007), but improved response inhibition and interference resolution (Beste et al., 2010a;Gajewski et al., 2012). These findings appear to tie Met carriers' deficits to fronto-hippocampal function whereas Val/Val carriers' deficits may rather reflect fronto-striatal function (Beste et al., 2010a;Gajewski et al., 2012;Getzmann et al., 2013). Animal studies also point to a dissociation of BDNF's effect on different neural circuits depending on direction and location of manipulations: Increasing BDNF in the hippocampus promotes hippocampal-dependent learning (Peters et al., 2010), whereas decreasing BDNF in the ventral tegmental area promotes reward sensitivity and presumably reward learning (Koo et al., 2012). ...
... For example, a 10-year follow-up study showed a faster decline in task-switching performance in Val/Val compared to Met carriers (Erickson et al., 2008), suggesting that behavioral deficits in Val/Val compared to Met carriers may have been more easily detected using IFJ-dependent cognitive tasks and in elderly subjects. This hypothesis is consistent with previous studies in healthy elderly subjects reporting behavioral deficits in Val/Val compared to Met carriers in cognitive tasks known to engage the IFJ, including the Stroop interference, auditory distraction and task-switching paradigms (Harris et al., 2006;Erickson et al., 2008;Gajewski et al., 2012;Getzmann et al., 2013). ...
Animal work implicates the brain-derived neurotrophic factor (BDNF) in function of the ventral striatum (VS), a region known for its role in processing valenced feedback. Recent evidence in humans shows that the BDNF Val66Met polymorphism modulates VS activity in anticipation of monetary feedback. However, it remains unclear whether the polymorphism impacts the processing of self-attributed feedback differently from feedback attributed to an external agent. In this study, we emphasize the importance of the feedback attribution because agency is central to computational accounts of striatum and cognitive accounts of valence processing. We used functional magnetic resonance imaging and a task, in which financial gains/losses are either attributable to performance (self-attributed, SA) or chance (externally-attributed, EA) to ask whether the BDNF Val66Met polymorphism predicts VS activity. We found that the BDNF Val66Met polymorphism influenced how feedback valence and agency information were combined in the VS and in the right inferior frontal junction (IFJ). Specifically, Met carriers' VS response to valenced feedback depended on agency information, while Val/Val carriers' VS response did not. This context-specific modulation of valence effectively amplified VS responses to SA losses in Met carriers. The IFJ response to SA losses also differentiated Val/Val from Met carriers. These results may point to a reduced allocation of attention and altered motivational salience to SA losses in Val/Val compared to Met carriers. Implications for major depressive disorder are discussed.
... decreased d frequency band total power and synchronization during an error related negativity (ERN) task) [49] and attention (i.e. P300 latency increase and amplitude reduction) [29,50]. ...
... As part of a larger investigation into the role of BDNF on synaptic and neural network activity in humans, we focused our investigation on electrophysiological markers including ERN, Mismatch Negativity (MMN), resting EEG activity/synchronization and P300. These EEG/ERP markers were selected because they have been shown to be sensitive to the BDNF Val66Met polymorphism [29,49,50], and/or impaired in neurodegenerative disorders including AD (e.g. [51,52]). ...
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.
... This suggests that the genetic effects on cognition are more pronounced as cognitive resources diminish during the ageing process, particularly for those carrying the Met allele. However, elderly people have also been shown to have better Stroop performance and enhanced brain activation when carrying the Met allele [16] and recent evidence links the homozygous Val allele of the Val66Met BDNF gene to deficits in working memory processes in healthy elderly [17]. Thus, the data linking BDNF on brain structure and function in elderly is inconsistent. ...
... Our data suggest that poorer performance on a working memory task and related brain differences are specifically associated with the Val allele rs6265 BDNF allele in an elderly Swedish cohort, and that carrying the Met allele may have neuro-protective effects. This supports recent findings linking the homozygous Val allele of the Val66Met BDNF gene to deficits in working memory processes in healthy elderly [17]. Furthermore, elderly Met carriers have been shown to be better at the Stroop task and show better brain function during tasks as measured by event related potentials [16]. ...
Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking.
367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF.
The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes.
The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly.
... The most frequently studied example of attentional capture is the disruptive effect of a single auditory deviant in an otherwise regular (and thus predictable) sequence of sounds, such as a sudden change in frequency. This auditory deviation effect has been studied extensively using the oddball paradigm (for a review see Parmentier, 2014), demonstrating not only disruption to memory performance but also delayed response times in speeded classification tasks or enhanced electrophysiological indicators of distraction (Escera et al., 1998;Getzmann et al., 2013;Leiva et al., 2016;Parmentier, 2016;Parmentier et al., 2008Parmentier et al., , 2018Wessel & Aron, 2013;Wessel et al., 2016). Importantly, acoustical deviants in both steady-state and changing-state sequences of irrelevant sound were also shown to disrupt performance in a serial recall task (Hughes et al., 2005(Hughes et al., , 2007(Hughes et al., , 2013Marois & Vachon, 2018;Vachon et al., 2012), suggesting independent and additive effects of changing-state sound and auditory deviants (with the deviation effect typically being smaller in magnitude than the changing-state effect). ...
The presence of task-irrelevant sound disrupts short-term memory for serial information. Recent studies found that enhanced perceptual task-encoding load (static visual noise added to target items) reduces the disruptive effect of an auditory deviant but does not affect the task-specific interference by changing-state sound, indicating that the deviation effect may be more susceptible to attentional control. This study aimed to further specify the role of attentional control in shielding against different types of auditory distraction, examining speech and nonspeech distractors presented in laboratory and Web based experiments. To further elucidate the role of controlled processes, we tested whether the detrimental effects of distractor sounds-and their modulation by attentional control-reach participants' awareness. We found that changing-state sound and auditory deviants in steady-state sound equally affected both objective recall performance and metacognitive confidence judgments but did not affect the accuracy of confidence judgments. Most importantly, across four experiments, an increase of task load (visual degradation of the to-be-remembered items) did not reduce either type of auditory distraction. A close replication of the original modulation of the deviation effect by perceptual task load (in an online environment) even revealed a stronger deviation effect at high task load, suggesting that the manipulation may have influenced cognitive load and the ability to control distractor interference in memory. In line with a unitary account of auditory distraction, the results suggest that although both types of distraction reach metacognitive awareness, they may be equally unrelated to perceptual load and the availability of attentional resources. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
... Typically, high blood pressure and cholesterol, as well as diabetes, induce cognitive decline during aging (see [6,7,177]). The role of environmental factors, beneficial or deleterious, may be reflected in BDNF protein secretion which respectively stimulates or inhibits endogenous neurogenesis, especially during aging [65,186]. ...
In the absence of any neuropsychiatric condition, older adults may show declining performance in several cognitive processes and among them, in retrieving and producing words, reflected in slower responses and even reduced accuracy compared to younger adults. To overcome this difficulty, healthy older adults implement compensatory strategies, which are the focus of this paper. We provide a review of mainstream findings on deficient mechanisms and possible neurocognitive strategies used by older adults to overcome the deleterious effects of age on lexical production. Moreover, we present findings on genetic and lifestyle factors that might either be protective or risk factors of cognitive impairment in advanced age. We propose that “aging modulating factors” (AMF) can be modified, offering
prevention opportunities against aging effects. Based on our review and this proposition, we introduce an integrative neurocognitive model of mechanisms and compensatory strategies for lexical production in older adults (entitled Lexical Access and Retrieval in Aging, LARA). The main hypothesis defended in LARA is that cognitive aging evolves heterogeneously and involves complementary domain-general and domain-specific mechanisms, with substantial inter-individual variability, reflected at behavioral, cognitive, and brain levels. Furthermore, we argue that the ability to compensate for the effect of cognitive aging depends on the amount of reserve specific to each individual which is, in turn, modulated by the AMF. Our conclusion is that a variety of mechanisms and compensatory strategies coexist in the same individual to oppose the effect of age. The role of reserve is pivotal for a successful coping with age-related changes and future research should continue to explore the modulating role of AMF.
... Moreover, EEG methods have shown that there are distinct fractions of information encoded in neurophysiological correlates, which overlap in time. These represent cognitive-emotional control and conflict monitoring and should be evaluated separately (36,38,(44)(45)(46)(47)(48). This can be done using residue iteration decomposition (RIDE), whereby standard event-related potentials are decomposed, resulting J o u r n a l P r e -p r o o f 6 in three distinct component clusters (49)(50)(51). ...
Background
Affective dysregulation (AD) or synonymously "irritability" is a transdiagnostic construct that serves as a diagnostic criterion in various childhood mental disorders. It is characterized by severe or persistent outbursts of anger and aggression. Emotional self-regulation is highly dependent on the ability to process relevant and ignore conflicting emotional information. Understanding neurophysiological mechanisms underlying impairment in AD may provide a starting point for research on pharmacological treatment options and evaluation of psychotherapeutic intervention.
Methods
N=120 children, aged 8 to 12 years (63 with AD and 57 typical-developed children, TD) were examined using an emotional Stroop task. Signal decomposed EEG-recordings providing information about the affected sensory-perceptual, response selection, or motor information processing stage were combined with source localisation.
Results
Behavioral performance revealed dysfunctional cognitive-emotional conflict monitoring in children with AD suggesting difficulties to differentiate between conflicting and non-conflicting cognitive-emotional information. This was confirmed by the EEG-data showing that they cannot intensify response selection processes during conflicting cognitive-emotional situations. TD children were able to do so and activated a functional-neuroanatomical network comprising the left inferior parietal cortex (BA40), right middle frontal (BA10) and right inferior/orbito-frontal (BA47) regions. Purely sensory-perceptual selection and motor execution processes were not modulated in AD as evidenced by Bayesian analyses.
Conclusions
Behavioral and EEG data suggest that children with AD cannot adequately modulate controlled response selection processes given emotionally ambiguous information. Which neurotransmitter systems underlie these deficits and how they can be improved are important questions for future research.
... For example, a large metaanalysis of 7000 heterogeneous participants reported no link between the BDNF Val66Met polymorphism and cognitive functions such as executive functioning, cognitive fluency and general intellectual functioning [39]. Conversely, a study using an auditory distraction paradigm-different, methodologically, from standard cognitive testing-has shown that BDNF Val homozygosity may be disadvantageous when inhibitory mechanisms are required, indicating that increased activation associated with the Val allele may not be advantageous for inhibitory effects processed in frontal pathways [40]. A recent systematic review on the topic has confirmed that BDNF Val66Met likely has some impact on cognitive function, although the specific direction is difficult to ascertain [41]. ...
Brain-derived neurotropic factor (BDNF) is an abundant and multi-function neurotrophin in the brain. It is released following neuronal activity and is believed to be particularly important in strengthening neural networks. A common variation in the BDNF gene, a valine to methionine substitution at codon 66 (Val66Met), has been linked to differential expression of BDNF associated with experience-dependent plasticity. The Met allele has been associated with reduced production of BDNF following neuronal stimulation, which suggests a potential role of this variation with respect to how the nervous system may respond to challenges, such as brain ageing and related neurodegenerative conditions (e.g., dementia and Alzheimer’s disease). The current review examines the potential of the BDNF Val66Met variation to modulate an individual’s susceptibility and trajectory through cognitive changes associated with ageing and dementia. On balance, research to date indicates that the BDNF Met allele at this codon is potentially associated with a detrimental influence on the level of cognitive functioning in older adults and may also impart increased risk of progression to dementia. Furthermore, recent studies also show that this genetic variation may modulate an individual’s response to interventions targeted at building cognitive resilience to conditions that cause dementia.
... Some previous reports have found positive effects of BDNF Met polymorphism on executive function performance in cognitively healthy individuals [51], but not in aMCI patients [52]. Recently, it has been shown that BDNF Val homozygosity may be disadvantageous when inhibitory mechanisms are required, indicating that Met allele may confer some benefit to its carriers for the executive functions processed in the frontostriatal pathways [53]. However, we could not find any beneficial effect of BDNF Met polymorphism among APOE 4 carriers, suggesting that 4 allele may contribute to abolish the positive effect of BDNF Met polymorphism on executive functions. ...
Apolipoprotein (APOE) ε4 is a well-known risk factor for late-onset Alzheimer disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age=72.2) were recruited from the Czech Brain Aging Study and, based on APOE and BDNF genes polymorphisms, were divided into 4 groups: ε4-BDNFVal/Val (n=37), ε4-BDNFMet (n=19), ε4+BDNFVal/Val (n=35), ε4+BDNFMet (n=16). All patients underwent clinical examination, magnetic resonance imaging and complex neuropsychological battery.
The combination of APOE 4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ε4+BDNFMet group. Our findings suggest that carriage of ε4+BDNFMet is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOE ε4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes.
... Greater performance in the spatial domain for the Val/Val genotype has been shown in previous work (McHughen et al., 2010), however, to our knowledge, this is the first study to demonstrate an advantage in the temporal domain of motor performance for the Val/Met genotype. Previously, an advantage for individuals with the Met allele had only been observed in a few select cognitive tasks (Gajewski, Hengstler, Golka, Falkenstein, & Beste, 2011Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013). The basis for these differences in motor performance is unknown, but may be related to dissimilarities in brain structure between the genotype groups (Bueller et al., 2006;Pezawas et al., 2004), which may result in functional differences. ...
Background:
Pairing a bout of high-intensity exercise with motor task practice can enhance motor learning beyond task practice alone, which is thought, in part, to be facilitated by an exercise-related increase in brain-derived neurotrophic factor (BDNF). The purpose of the current study was to examine the effect of different exercise intensities on BDNF levels and motor learning while controlling for exercise-related energy expenditure.
Methods:
Forty-eight young, healthy participants were assigned to one of three groups: high-intensity exercise [High], low-intensity exercise [Low], or quiet rest [Rest]. The duration of the exercise bouts were individually adjusted so that each participant expended 200 kcals regardless of exercise intensity. BDNF was measured before and after exercise or rest. After exercise or rest, all participants practiced a 3-dimensional motor learning task, which involved reach movements made to sequentially presented targets. Retention was tested after 24-h. BDNF genotype was determined for each participant to explore its effects on BDNF and motor learning.
Results:
All participants equally improved performance, indicated by a reduction in time to complete the task. However, the kinematic profile used to control the reach movement differed by group. The Rest group travelled the shortest distance between the targets, the High group had higher reach speed (peak velocity), and the Low group had earlier peak velocities. The rise in BDNF post-exercise was not significant, regardless of exercise intensity, and the change in BDNF was not associated with motor learning. The BDNF response to exercise did not differ by genotype. However, performance differed between those with the polymorphism (Met carriers) and those without (Val/Val). Compared to the Val/Val genotype, Met carriers had faster response times throughout task practice, which was supported by higher reach speeds and earlier peak velocities.
Conclusion:
Results indicated that both low and high-intensity exercise can alter the kinematic approach used to complete a reach task, and these changes appear unrelated to a change in BDNF. In addition, the BDNF genotype did not influence BDNF concentration, but it did have an effect on motor performance of a sequential target reach task.
... In the current study, Met/-allele carriers clearly displayed enhanced performance of attention and inhibition compared with the Val/Val carrier group; however, this association was found irrespective of cognitive training. This finding aligns with previous research in older adults suggesting enhanced controlled response and inhibition in Met/-allele carriers compared with Val/Val carriers (Gajewski et al., 2012;Getzmann et al., 2013). BDNF was not found to moderate the training response for memory, visuospatial function, or verbal fluency. ...
Given the increase in research suggesting benefit following cognitive training in older adults, researchers have started to investigate the potential moderating role of genetic polymorphisms on transfer effects. The objective of this study was to evaluate the moderating effect of catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) polymorphisms on transfer effects following a single-domain or multi-domain training intervention in healthy community-dwelling older adults. A total of 104 men and women living in Shanghai were randomized to a multi-domain or a single-domain cognitive training (SDCT) group. COMT rs4818 SNP and the BDNF rs6265 SNP were analyzed from blood. At pre-intervention, post-intervention and at 6-month follow-up, participants completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Color-Word Stroop Test (CWST), the Trails Making Test (TMT) and the Visual Reasoning Test (VRT). COMT was found to moderate immediate memory transfer effects following single-domain training only, with G/- carriers displaying greater benefits than C/C carriers. BDNF was found to moderate attention and inhibition independent of the training, with Met/- carriers displaying better performance than Val/Val carriers. Overall, individualizing training methods with full consideration of genetic polymorphisms may promote the maximization of cognitive training benefits.
... Multiple studies of human subjects have indicated that BDNF Met carriers have compromised cognitive function (Egan et al., 2003;Tsai et al., 2004;Bath and Lee, 2006;Miyajima et al., 2008;Schofield et al., 2009). However, there have also been reports of benefits to executive functions (Erickson et al., 2008;Ventriglia et al., 2002;Matsushita et al., 2005;Beste et al., 2010a, b;Gajewski et al., 2011Gajewski et al., , 2012Alfimova et al., 2012;Getzmann et al., 2013). In one example, Beste et al. found that carriers of the Met allele had fewer false alarms on a go/no-go task, which correlated with larger no-go-N2 event related potentials (ERPs) in Met carriers (Beste et al., 2010a). ...
• A common human polymorphism in the gene that encodes brain derived neurotrophic factor (BDNF), Val66Met, is considered a marker of vulnerability for mental health issues and has been associated with cognitive impairment. An alternate framework has been proposed in which “risk alleles” are reinterpreted as “plasticity alleles” that confer vulnerability in adverse environments and positive effects in neutral or positive environments (Belsky et al., 2009). These frameworks produce divergent predictions for tests of learning and cognitive flexibility. Here, we examined multiple aspects of learning and cognitive flexibility in a relatively new BDNF Val66Met mouse model (BDNF Val68Met, Warnault et al., 2016), including multiple choice discrimination and reversal, go/no-go learning and reversal, and appetitive extinction learning. We found that mice homozygous for the Met allele show more efficient reversal learning in two different paradigms, but learn at rates comparable to Val homozygotes on the multiple choice discrimination task, a go/no-go task, and in appetitive extinction. Our results dissociate reversal performance from go/no-go learning and appetitive extinction and support the plasticity allele framework that suggests BDNF Met carriers are potentially more sensitive to changes in the environment.
... It is also necessary to investigate how the BDNF polymorphism affects the neurons and CNS phenotypes including in the retina in normal healthy subjects and potential effects with age. BDNF polymorphism has indeed been suggested to have a role in geriatric depression [127], LOAD [1], age-related changes in reasoning skills and executive function [54,55], goaldirected behaviour in the elderly [128], and reduced Stroop interference [129], and altered cognitive abilities in the elderly [130]. Thus, aging exacerbates susceptibility to neurological diseases and may amplify the effects of the polymorphism. ...
Brain-derived neurotrophic factor (BDNF) has a unique role in the neuronal development, differentiation, and survival in the developing and adult nervous system. A common single-nucleotide polymorphism in the pro-region of the human BDNF gene, resulting in a valine to methionine substitution (Val66Met), has been associated with the susceptibility, incidence, and clinical features of several neurodegenerative disorders. Much research has been dedicated to evaluating the effects of polymorphism in the past decade, and functional effects of this genetic variation. A better understanding of how this naturally occurring polymorphism associates with or influences physiology, anatomy, and cognition in both healthy and diseased adults in neurodegenerative conditions will help understand neurochemical mechanisms and definable clinical outcomes in humans. Here we review the role and relevance of the BDNF Val66Met polymorphism in neurodegenerative diseases, with particular emphasis on glaucoma, multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Several controversies and unresolved issues, including small effect sizes, possible ethnicity, gender, and age effects of the BDNF Val66Met are also discussed with respect to future research.
... However, the role of the DA system (especially in the PFC) cannot be seen isolated from the effects of other neurotransmitter systems, e.g., the norepinephrine (NE system), because NE and DA exert powerful biological effects by activating converging synaptic pathways in PFC circuitry (Xing et al. 2016). Task-switching processes may, therefore, be modulated by the norepinephrine (NE) system for a number of reasons: switch costs likely represent an active reconfiguration process (Monsell 2003), involving different cognitive subprocesses, such as shifting of attention, conflict monitoring and response selection, or the inhibition of interference from the previous irrelevant response sets (Monsell 2003;Kiesel et al. 2010;Getzmann et al. 2013). Conflict monitoring and inhibition processes have been shown to be modulated by the NE system (Robinson et al. 2008;Chamberlain et al. 2009;Steenbergen et al. 2015b;Mückschel et al. 2016;Beste et al. 2016;Chmielewski et al. 2017). ...
Cognitive flexibility is a major requirement for successful goal-directed behavior and their neurobiological underpinnings are becoming better understood. However, the role of the norepinephrine system during task switching is largely enigmatic, despite neurobiological considerations make it likely that the norepinephrine system likely plays an important role. Theoretical considerations, also suggest that the norepinephrine system mainly modulates task switching processes, when these rely upon working memory mechanisms. This topic was examined in the current system neurophysiological study integrating event-related potential (ERP) with pupil diameter data as a proximate the norepinephrine system activity. Combined with source localization methods, human brain structure, brain function and phasic modulations by an important neurobiological system were integrated. The results show that cognitive-neurophysiological subprocesses during the actual switching processes, reflected by the N2 and P3 ERP components, are not modulated by the norepinephrine system. Rather, this system modulates preparatory processes in the fore period of stimuli signaling possible switches of response sets. The source localization results show that this is achieved by modulating neural processes in the temporo-parietal junction (BA40). Importantly, these phasic modulatory effects of the norepinephrine system were only evident when working memory processes had to be used to guide the selection of the appropriate responses for task switching.
... It can be supposed that distracting events are stored more in the carriers of Val allele than Met/Met homozygous patients, ultimately impairing attention in the distraction-orientation-refocusing cycle. Getzmann et al. (2013) suggested that response inhibition capability prevents the processing of deviant stimuli which indirectly protect objective-based representations (or learned materials) from the interference phenomenon. Therefore, it seems logical that response inhibition be less powerful in Val/Val genotype. ...
It is suggested that brain-derived neurotrophic factor (BDNF) has a protective role against brain lesion after an ischemic stroke (IS); however, there is inadequate information as to the role of BDNF in cognitive impairments following IS. This study evaluate the effects of IS and BDNF (Val66Met) gene polymorphism on global and multi-domain (attention, memory, verbal fluency, language, and visuospatial abilities) cognitive functions. In a case-control study, we selected 206 patients with IS who were consecutively discharged from Poursina Hospital in the north of Iran. The patients were compared with the control group comprised of 200 individuals who were referred to the Social Service Retirees Center in Rasht City. The comparison was made in terms of genetic variant BDNF Val66Met and also their scores in the Addenbrooke’s Cognitive Examination-Third Edition (ACE-III). The patients compared with the control group were suffering from higher rates of global cognitive impairment. [F(1398) = 38.29, ή2 = 0.09, P < 0.0001] and lower scores in domains of memory [F(1383) = 39.57, ή2 = 0.094, P < 0.0001], language abilities [F(1383) = 27.05, ή2 = 0.066, P < 0.0001], and visuospatial functions [F(1.383) = 9.54, ή2 = 0.024, P = 0.002]. In addition, carriers of at least one Val allele were suffering from greater rates of global cognitive impairment than Met/Met homozygous [F(1398) = 12.41, ή2 = 0.03, P < 0.0001], and their scores in the domains of attention [F(1383) = 13.43, ή2 = 0.034, P < 0.0001] and language abilities were found to be lower than that of the control group [F(1383) = 11.73, ή2 = 0.03, P = 0.001]. However, the interactive effects of BDNF Val66Met × groups were not statistically significant (P > 0.05). The impairments are especially evident in domains of memory, language abilities, and visuospatial functions. Furthermore, there exists a relationship between the presence of at least one BDNF Val allele and impairment in the global cognitive functions, attention, and language domains. Nonetheless, BDNF Val66Met polymorphism does not seem to have a role in any specific cognitive impairment in IS patients.
... These results support previous claims of interaction between these genes in other complex cognitive tasks such as visual working memory [21] and in differences in connectivity of several resting-state networks [14,22]. The involuntary control of attention seems to be highly influenced by differential gene expression in fronto-striatal circuits, since a recent report has shown that genetic variation in the BDNF gene affects performance in an auditory distraction paradigm similar to ours [58]. Furthermore, the reported electrophysiological correlates of the control of attention might constitute a reliable endophenotypic marker of the DA system, and could help to isolate in near future dysfunction in the human DA system. ...
Attention capture by potentially relevant environmental stimuli is critical for human survival, yet it varies considerably among individuals. A large series of studies has suggested that attention capture may depend on the cognitive balance between maintenance and manipulation of mental representations and the flexible switch between goal-directed representations and potentially relevant stimuli outside the focus of attention; a balance that seems modulated by a prefrontostriatal dopamine pathway. Here, we examined inter-individual differences in the cognitive control of attention through studying the effects of two single nucleotide polymorphisms regulating dopamine at the prefrontal cortex and the striatum (i.e., COMTMet108/158Val and ANKK1/DRD2TaqIA) on stimulus-driven attention capture. Healthy adult participants (N = 40) were assigned to different groups according to the combination of the polymorphisms COMTMet108/158Val and ANKK1/DRD2TaqIA, and were instructed to perform on a well-established distraction protocol. Performance in individuals with a balance between prefrontal dopamine display and striatal receptor density was slowed down by the occurrence of unexpected distracting events, while those with a rather unbalanced dopamine activity were able maintain task performance with no time delay, yet at the expense of a slightly lower accuracy. This advantage, associated to their distinct genetic profiles, was paralleled by an electrophysiological mechanism of phase-resetting of gamma neural oscillation to the novel, distracting events. Taken together, the current results suggest that the epistatic interaction between COMTVal108/158Met and ANKK1/DRD2 TaqIa genetic polymorphisms lies at the basis of stimulus-driven attention capture.
... Response-selection processes, indicated by the N2 (which indexes the resolution of task-set conflict and the selection of an appropriate response when a task has to be switched (see, e.g. Karayanidis et al. 2003;Gajewski et al. 2010a;Getzmann et al. 2013)), also represent important cognitive subprocesses during task switching (Beste et al. 2010b;Gajewski et al. 2010aGajewski et al. , 2011. As the N2 is hence not directly modulated by working memory processes it is possible that processes reflected by the N2 are not differentially modulated between adolescents with ASD and TD during memory-based versus non-memorybased task switching. ...
Objectives: Autism Spectrum Disorder (ASD) is associated with repetitive and stereotyped behavior, suggesting that cognitive flexibility may be deficient in ASD. A central, yet not examined aspect to understand possible deficits in flexible behavior in ASD relates i) to the role of working memory and ii) to neurophysiological mechanisms underlying behavioral modulations.
Methods: We analyzed behavioral and neurophysiological (EEG) correlates of cognitive flexibility using a task switching paradigm with and without working memory load in adolescents with ASD and typically developing controls (TD).
Results: Adolescents with ASD vs TD show similar performance in task switching with no memory load, indicating that “pure” cognitive flexibility is not in deficit in adolescent ASD. However performance during task repetition decreases with increasing memory load. Neurophysiological data reflect the pattern of behavioral effects, showing modulations in P2 and P3 event-related potentials.
Conclusions: Working memory demands affect repetitive behavior while processes of cognitive flexibility are unaffected. Effects emerge due to deficits in preparatory attentional processes and deficits in task rule activation, organization and implementation of task-sets when repetitive behavior is concerned. It may be speculated that the habitual response mode in ASD (i.e. repetitive behavior) is particularly vulnerable to additional demands on executive control processes.
... Unfortunately, studies with healthy elderly subjects represent a challenge in this field. Finally, it is already known that the BDNF Val66Met polymorphism has effects on other cognitive domains besides memory, including distinct components of executive functions, 35,38 reasoning, 16 attention, 39 and visualauditory working memory. 40 Therefore, we were not able to restrict the effects of this SNP to memory. ...
Objective::
Memory impairment is an important contributor to the reduction in quality of life experienced by older adults, and genetic risk factors seem to contribute to variance in age-related cognitive decline. Brain-derived neurotrophic factor (BDNF) is an important nerve growth factor linked with development and neural plasticity. The Val66Met polymorphism in the BDNF gene has been associated with impaired episodic memory in adults, but whether this functional variant plays a role in cognitive aging remains unclear. The purpose of this study was to investigate the effects of the BDNF Val66Met polymorphism on memory performance in a sample of elderly adults.
Methods::
Eighty-seven subjects aged > 55 years were recruited using a community-based convenience sampling strategy in Porto Alegre, Brazil. The logical memory subset of the Wechsler Memory Scale-Revised was used to assess immediate verbal recall (IVR), delayed verbal recall (DVR), and memory retention rate.
Results::
BDNF Met allele carriers had lower DVR scores (p = 0.004) and a decline in memory retention (p = 0.017) when compared to Val/Val homozygotes. However, we found no significant differences in IVR between the two groups (p = 0.088).
Conclusion::
These results support the hypothesis of the BDNF Val66Met polymorphism as a risk factor associated with cognitive impairment, corroborating previous findings in young and older adults.
... S'il s'avère que les résultats aient montré des différences, les données cognitives relevées ne dépendent pas toujours des mêmes fonctions. D'après certaines études, les fonctions des circuits fronto-striataux seraient rendues plus efficaces chez les personnes âgées porteuses de l'allèle Met (Gajewski, Hengstler, Golka, Falkenstein, & Beste, 2011Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013 ;Harris & Deary, 2011 ;Laukka et al., 2013 ;Tsai et al., 2008). Selon Beste, Baune, Domschke, Falkenstein et Konrad (2010), les effets du BDNF pourraient prendre des voies neuronales diverses insuffisamment élucidées. ...
A Systematic Review of Programmes that Promote Adherence to Regular Physical Activity in the Elderly : The Role of Affective Barriers
Research examining relevant variables that influence adherence to programmes designed to increase regular physical activity in the elderly is abundant. The purpose of the present review was to determine whether affective barriers associated with individuals’ expectations to engage in regular physical activity in the +65 years old had been considered and, if so how they were integrated in the development of such intervention programmes.
Amongst the 1195 citations identified, eight studies only were retained. These studies highlighted interpersonal influence as a critical variable of the programmes promoting regular physical activity amongst the +65. Furthermore, findings suggest that the affective dimension and interpersonal emotional regulation need consideration when developing such programmes.
... S'il s'avère que les résultats aient montré des différences, les données cognitives relevées ne dépendent pas toujours des mêmes fonctions. D'après certaines études, les fonctions des circuits fronto-striataux seraient rendues plus efficaces chez les personnes âgées porteuses de l'allèle Met (Gajewski, Hengstler, Golka, Falkenstein, & Beste, 2011Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013 ;Harris & Deary, 2011 ;Laukka et al., 2013 ;Tsai et al., 2008). Selon Beste, Baune, Domschke, Falkenstein et Konrad (2010), les effets du BDNF pourraient prendre des voies neuronales diverses insuffisamment élucidées. ...
... Given this, and the fact that we (Noohi et al., 2014) and others (Pearson-Fuhrhop et al., 2013) have combined across these genes to compute a "number of high performance alleles" score (NHPA), we do not present the single polymorphism results here, but only focus on NHPA effects. Similar to some previous reports (Barton et al., 2014;Erickson et al., 2008;Gajewski et al., 2011;Getzmann et al., 2013), we found paradoxical results for the BDNF met allele in relation to behavior. That is, we found that BDNF met homozygotes performed superior to the val allele carriers in the sequence learning task. ...
The interactive association of age and dopaminergic polymorphisms on cognitive function has been studied extensively. However, there is limited research on whether age interacts with the association between genetic polymorphisms and motor learning. We examined a group of young and older adults' performance in three motor tasks: explicit sequence learning, visuomotor adaptation, and grooved pegboard. We assessed whether individuals' motor learning and performance were associated with their age and genotypes. We selected three genetic polymorphisms: Catechol-O-Methyl Transferase (COMT val158met) and Dopamine D2 Receptor (DRD2 G>T), which are involved with dopaminergic regulation, and Brain Derived Neurotrophic Factor (BDNF val66met) that modulates neuroplasticity and has been shown to interact with dopaminergic genes. Although the underlying mechanisms of the function of these three genotypes are different, the high performance alleles of each have been linked to better learning and performance. We created a composite polygene score based on the Number of High Performance Alleles (NHPA) that each individual carried. We found several associations between genetic profile, motor performance, and sensorimotor adaptation. More importantly, we found that this association varies with age, task type, and engagement of implicit versus explicit learning processes.
... It is likely that attentional selection processes are changed in the current trials (i.e. the last trials of a given trial triplet). First of all, (Sinai et al. 2007) reported that the N1 at parietal sites, which is known to reflect attentional selection processes such as focusing on task-relevant stimuli (Beste et al. 2010a;Getzmann et al. 2013;Herrmann and Knight 2001;Hillyard and Anllo-Vento 1998;Luck et al. 1990;Wascher and Beste 2010), was larger in the BI condition than in the control condition. Moreover, attentional processes have an important gating function (Banich 1998;Vidyasagar 1999). ...
Task switching is regularly required in our everyday life. To succeed in switching, it is important to inhibit the most recently performed task and instead activate the currently relevant task. The process that inhibits a recently performed task when a new task is to be performed is referred to as ‘backward inhibition’ (BI). While the BI effect has been subject to intense research in cognitive psychology, little is known about the neuronal mechanisms that are related to the BI effect and those that relate to differences in the magnitude of the BI effect. In the current study, we examined the system neurophysiological basis of BI processes using event-related potentials (ERPs) and sLORETA by also taking inter-individual differences in the magnitude of the BI into account. The results suggest that BI processes and inter-individual differences in them strongly depend upon attentional selection mechanisms (reflected by N1-ERP modulations in the current task/trial) mediated via networks consisting of extrastriate occipital areas, the temporo-parietal junction and the inferior frontal gyrus. Other processes and mechanisms related to conflict monitoring, response selection, or the updating, organization and implementation of a new task-set (i.e. N2 and P3 processes) were not shown to be modulated by BI processes and differences in their magnitude, as evoked with a common BI paradigm.
... Interestingly, an association between auditory distraction in older adults and a genetic polymorphism known to underlie aging effects, the brain-derived-neurotrophicfactor (BDNF) Val66Met polymorphism, has recently been demonstrated (Getzmann et al. 2013b). In particular, the Val/Val genotype confers disadvantages to its carriers that are mainly based on response selection processes being more vulnerable against interference from distractors than the Val/Met genotype group. ...
N-Acetyltransferase 2 (NAT2) genotype is associated with age-related declines in basic sensory hearing functions. However, the possible modulatory role of NAT2 for higher cognitive functions has not yet been studied. We tested auditory goal-directed behavior and attentional control in 120 NAT2 genotyped subjects (63-88 years), using an auditory distraction paradigm in which participants responded to the duration of long and short tone stimuli. We studied involuntary shifts in attention to task-irrelevant deviant stimuli and applied event-related potentials (ERPs) to examine which cognitive subprocesses are affected by NAT2 status on a neurophysiological level. Relative to the standard stimuli, deviant stimuli decreased performance in the recently described ultra-slow acetylators (NAT2*6A and *7B): The increase in error-corrected reaction times (a combined measure of response speed and accuracy) in ultra-slow acetylators (254 ms increase) was more than twice as high as in the rapid acetylator reference group (111 ms increase; p < 0.01). The increase was still higher than in the other slow acetylators (149 ms increase, p < 0.05). In addition, clear differences were found in the ERP results: Ultra-slow acetylators showed deficits specifically in the automatic detection of changes in the acoustic environment as evidenced by reduced mismatch negativity (MMN, p < 0.005 compared to rapid acetylators). Refocussing of attention after a distracting event was also impaired in the ultra-slow acetylators as evidenced by a reduced re-orienting negativity (RON, p < 0.01 compared to rapid acetylators). In conclusion, the ultra-slow acetylation status was associated with reduced higher cognitive functions.
... Friedman et al. (2007) suggest that older adults involve this system in a more undifferentiated manner than younger adults that may lead to resource deficits in other processes underlying task switching. Other authors interpreted an enhanced P3a as an index of increased distractibility in aging (e.g., Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013). ...
The study investigated the neuronal mechanisms of age-related changes in mixing costs during memory-based task switching with two levels of working memory (WM) load. Forty-eight healthy younger and 45 healthy older participants performed a memory based (high WM load) and a memory plus cue based (low WM load) switching task while event-related brain potentials (ERPs) were registered. Older adults revealed larger mixing costs in both reaction time (RT) and accuracy at higher WM loads than younger adults. The presence of explicit cues substantially reduced age differences in mixing costs for accuracy but not for RT. Similarly, no age differences regarding local switch costs were found at lower WM load. Surprisingly, larger RT local costs in younger adults than in older adults were found in the memory-based block. The CNV was reduced under high WM load and positively correlated with accuracy mixing costs in older adults. The target-locked occipital N1 and fronto-central P2 were larger in older adults relative to younger adults irrespective of WM load. The P2 latency reflected the pattern of switch costs observed in behavioral data. Moreover, P2 latency positively correlated with RT mixing costs in older adults. Elderly also showed a delayed N2 and a delayed and reduced P3b. The results suggest that age-related differences in mixing costs may be partially due to a less efficient task preparation and task set maintenance (CNV) in elderly. However, elderly attempted to compensate for these deficits by permanent activation of mechanisms relating to stimulus encoding (N1) and task-set retrieval (P2). Finally, the delayed fronto-central N2 as well as the delayed and reduced parietal P3b strongly suggest delays of response selection and working memory updating in elderly due to an increase in selection threshold or in response selection variability constituting the performance decline.
... between locations (e.g., Blum, Lutz, & Jäncke, 2007), and in particular event-related potentials (ERPs; e.g., Berti & Wühr, 2012;Blom, Wiering, & Van der Lubbe, 2012;Boksem, Kostermans, Tops, & De Cremer, 2012, Sulykos, KecskØs-Kovµcs, & Czigler, 2013Wronka & Walentowska, 2014), structural and functional magnetic resonance imaging (fMRI; e.g., Eyler, Sherzai, Kaup, & Jeste, 2011;Fjell & Walhovd, 2010), and more recently near-infrared spectroscopy (NIRS; e.g., Fabiani, Gordon, Maclin, Pearson, Brumback-Peltz, Low, McAuley, Sutton, Kramer, & Gratton, 2014). Finally, genetic methods are increasingly important and show the profound influence of genetic variations on cognition in elderly (Gajewski, Hengstler, Golka, Falkenstein, & Beste, 2013;Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013). All those methods have been used in addition to behavioral and neuropsychological methods. ...
... Middle-aged and older adults discriminated the duration of short and long tones that were either of highprobability standard frequency or of low-probability deviant frequencies (e.g., Schrçger & Wolff, 1998). These deviant stimuli have been shown to reliably evoke distraction effects in previous studies Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013;. The present study focused on the effect of deviant stimuli on the processing of standard stimuli following the deviant. ...
The presentation of a task-irrelevant deviant (novel) stimulus among otherwise repeated standard stimuli usually reduces performance not only for the deviant stimulus, but also for the standard following that deviant. Here, the so-called post-deviance distraction was investigated in 58 middle-aged and 52 old adults, using an auditory duration discrimination task and event-related potential (ERP) measures. After a deviant stimulus, the participants showed a decrease in performance in the subsequent standard stimulus. This effect was more pronounced in the old, than middle-aged, group. Relative to the standard stimuli preceding the deviant, post-deviant standards triggered a chain of mismatch negativity (MMN), P3a, and reorienting negativity (RON). While MMN and P3a did not differ in old and middle-aged adults, older participants showed a delayed RON. Assuming the RON to reflect processes of general task or feature reconfiguration and updating, these results suggest a delay in orienting-reorienting mechanisms as possible source of increased post-deviance distraction in elderly.
... Furthermore, increased gamma-band activity has been detected above the frontal scalp and the posterior parietal regions under incompatibility conditions (Kieffaber and Cho, 2010). Concerning the neurobiochemical levels, the dopamine system (Krämer et al., 2007), as well as systems modulating the dopamine system appear to be important for conflict monitoring functions (Baune et al., 2010a,b;Beste et al., 2010b,c;Gajewski et al., 2013;Getzmann et al., 2013). Molecular genetics studies have shown that subjects displaying fewer tandem repeats in the promoter region of the serotonin transporter gene (5-HTTLPR) or a single-nucleotide polymorphism (rs25531) in 5-HTTLPR exhibit impaired conflict monitoring during a flanker task (Holmes et al., 2010). ...
Autism spectrum disorders (ASDs) encompass a range of syndromes that are characterised by social interaction impairments, verbal and nonverbal communication difficulties, and stereotypic or repetitive behaviours. Although there has been considerable progress in understanding the mechanisms underlying the changes in the 'social' and 'communicative' aspects of ASD, the neurofunctional architecture of repetitive and stereotypic behaviours, as well as other cognitive domains related to response and action control, remain poorly understood. Based on the findings of neurobiological and neuroanatomical alterations in ASD and the functional neuroanatomy and neurobiology of different action control functions, we emphasise that changes in action control processes, including response inhibition, conflict and response monitoring, task switching, dual-tasking, motor timing, and error monitoring, are important facets of ASD. These processes must be examined further to understand the executive control deficits in ASD that are related to stereotypic or repetitive behaviours as a major facet of ASD. The review shows that not all domains of action control are strongly affected in ASD. Several factors seem to determine the consistency with which alterations in cognitive control are reported. These factors relate to the relevance of neurobiological changes in ASD for the cognitive domains examined and in how far action control relies upon the adjustment of prior experience. Future directions and hypotheses are outlined that may guide basic and clinical research on action control in ASD.
... A strength of this cross-sectional design, however is the sampling from the whole adult lifespan, rather than using the more common, but limited extreme age group comparison approach, which cannot explore age trajectories across the lifespan, nor can examine linear age x genotype interactions. Second, several studies have found that BDNF val66met polymorphism also exerts effects on domains of cognition besides memory: reasoning (Harris et al., 2006), executive functions (Erickson et al., 2008), task-switching (Gajewski et al., 2011), attention (Getzmann et al., 2013), and processing speed (Ghisletta et al., 2014;. Thus, the effect of BDNF is likely not selective to memory, per se, but impacts other cognitive processes, that may in turn relate to memory processes. ...
... Furthermore, stimulation methods influencing neural activity during cognitive processing such as TMS and tDCS are increasingly important in aging research (Hummel et al. 2010;Fujiyama et al., 2012). Finally, genetic methods are increasingly important and show the profound influence of genetic variations, such as the COMT Val 158 Met polymorphism (e.g., Gschwendtner et al., 2012) and BDNF Val 66-Met polymorphism on cognition and in elderly (Gajewski, Hengstler, Golka, Falkenstein, & Beste, 2011;Getzmann et al., 2013). All those methods have been used in addition to behavioral and neuropsychological methods in many of the studies that had been reported at the first Aging & Cognition Conference and were presented at the second as well. ...
Provides a summary for the collection of abstracts from the International Conference "Aging & Cognition." The abstracts examine various topics related to aging and cognition. (PsycINFO Database Record (c) 2013 APA, all rights reserved)
... For example, Berti et al. (2013) used inter-trial intervals that were about twice as long as those used in other studies, perhaps encouraging participants to privilege response accuracy and thereby increasing the probability of distraction showing in response times. Other possible factors may include variations in the older adults' characteristics Psychological Research across studies with respect to variables such as their genetic profile (Getzmann, Gajewski, Hengstler, Falkenstein, & Beste, 2013c), their level of cardio-vascular fitness (Getzmann, Falkenstein, & Gajewski, 2013a), or the extent to which they practice cognitively taxing activities such as video games (Mayas, Parmentier, Andrés, & Ballesteros, 2014). Under what conditions aging increases deviance distraction when irrelevant and target stimuli are auditory and form part of the same perceptual object remains therefore unclear. ...
Aging is typically considered to bring a reduction of the ability to resist distraction by task-irrelevant stimuli. Yet recent work suggests that this conclusion must be qualified and that the effect of aging is mitigated by whether irrelevant and target stimuli emanate from the same modalities or from distinct ones. Some studies suggest that aging is especially sensitive to distraction within-modality while others suggest it is greater across modalities. Here we report the first study to measure the effect of aging on deviance distraction in cross-modal (auditory-visual) and uni-modal (auditory-auditory) oddball tasks. Young and older adults were asked to judge the parity of target digits (auditory or visual in distinct blocks of trials), each preceded by a task-irrelevant sound (the same tone on most trials-the standard sound-or, on rare and unpredictable trials, a burst of white noise-the deviant sound). Deviant sounds yielded distraction (longer response times relative to standard sounds) in both tasks and age groups. However, an age-related increase in distraction was observed in the cross-modal task and not in the uni-modal task. We argue that aging might affect processes involved in the switching of attention across modalities and speculate that this may due to the slowing of this type of attentional shift or a reduction in cognitive control required to re-orient attention toward the target's modality.
... In this regard recent molecular genetic association studies show that visual sensory memory is modulated by genetic polymorphisms encoding for neurotrophic factors and receptors highly expressed in the striatum and of relevance to glutamatergic neural transmission (e.g. Arning et al., 2014 ;Beste et al. , 2012Beste et al. , , 2011Getzmann et al., 2013 ). However, we show that there could exist an "enhanced" selection state due to NMDA sensitivity compensating for cell-loss. ...
Paradoxically enhanced cognitive processes in neurological disorders provide vital clues to understanding neural function. However, what determines whether the neurological damage is impairing or enhancing is unclear. Here we use the performance of patients with two disorders of the striatum to dissociate mechanisms underlying cognitive enhancement and impairment resulting from damage to the same system. In a two-choice decision task, Huntington’s disease patients were faster and less error prone than controls, yet a patient with the rare condition of benign hereditary chorea (BHC) was both slower and more error prone. EEG recordings confirmed significant differences in neural processing between the groups. Analysis of a computational model revealed that the common loss of connectivity between striatal neurons in BHC and Huntingon’s disease impairs response selection, but the increased sensitivity of NMDA receptors in Huntingon’s disease potentially enhances response selection. Crucially the model shows there is a critical threshold for increased sensitivity: below that threshold, impaired response selection results. Our data and model thus predict that specific striatal malfunctions can contribute to either impaired or enhanced selection, and provide clues to solving the paradox of how Huntingon’s disease can lead to both impaired and enhanced cognitive processes.
... Interestingly, an association between auditory distraction in older adults and a genetic polymorphism known to underlie aging effects, the brain-derived-neurotrophicfactor (BDNF) Val66Met polymorphism, has recently been demonstrated (Getzmann et al. 2013b). In particular, the Val/Val genotype confers disadvantages to its carriers that are mainly based on response selection processes being more vulnerable against interference from distractors than the Val/Met genotype group. ...
Numerous studies have analyzed the impact of N-acetyltransferase 2 (NAT2) polymorphisms on drug efficacy, side effects as well as cancer risk. Here, we present the state of the art of deriving haplotypes from polymorphisms and discuss the available software. PHASE v2.1 is currently considered a gold standard for NAT2 haplotype assignment. In vitro studies have shown that some slow acetylation genotypes confer reduced protein stability. This has been observed particularly for G191A, T341C and G590A. Substantial ethnic variations of the acetylation status have been described. Probably, upcoming agriculture and the resulting change in diet caused a selection pressure for slow acetylation. In recent years much research has been done to reduce the complexity of NAT2 genotyping. Deriving the haplotype from seven SNPs is still considered a gold standard. However, meanwhile several studies have shown that a two-SNP combination, C282T and T341C, results in a similarly good distinction in Caucasians. However, attempts to further reduce complexity to only one 'tagging SNP' (rs1495741) may lead to wrong predictions where phenotypically slow acetylators were genotyped as intermediate or rapid. Numerous studies have shown that slow NAT2 haplotypes are associated with increased urinary bladder cancer risk and increased risk of anti-tuberculosis drug-induced hepatotoxicity. A drawback of the current practice of solely discriminating slow, intermediate and rapid genotypes for phenotype inference is limited resolution of differences between slow acetylators. Future developments to differentiate between slow and ultra-slow genotypes may further improve individualized drug dosing and epidemiological studies of cancer risk.
... These cortico-striatal circuits have frequently been shown to undergo degenerative changes in aging (e.g., Buckner, 2004), which likely underlies the susceptibility in elderly individuals to distracting stimuli from different sensory modalities leading to declines in goal-directed behavior (Getzmann et al., 2013a;Horvath et al., 2009;Ruzzoli et al., 2012). Besides changes in structural neuroanatomy, also changes in catecholaminergic neural transmission occur in aging (for review : Bäckman et al., 2010). ...
The val66met polymorphism of the brain‐derived neurotrophic factor (BDNF) gene has been identified as a potential moderator for the relationship between chronic stress and executive functioning. However, whether the presence of the met allele increases cognitive vulnerability or resilience to stress has yet to be determined. Given the established effects of autonomic activity and psychological arousal on executive functioning, in the present study, 56 healthy university students completed self‐report measures of chronic stress, positive arousal (vigour) and negative arousal (anxiety) and measured heart‐rate variability to quantify autonomic activity. Participants then completed a cognitive test battery that measured attention, decision‐making, visual learning and working memory. Regression analyses demonstrated that Val/met participants performed better on attention and working memory tasks than Val/val participants, but no differences were seen in decision‐making and visual learning. Further, Val/met participants were protected from stress‐related differences in attention seen in Val/val participants. Val66met was not associated with physiological or psychological arousal. This study demonstrates that val66met plays an important but selective role in cognitive performance.
Brain-derived neurotrophic factor is a neurotrophin known to have prominent roles in maintenance, growth, and survival of neurons in the central nervous system. Brain-derived neurotrophic factor is involved in modulating synaptic plasticity and connectivity in the brain, and dysregulation of the molecule has been implicated in enhanced vulnerability to neurodegeneration and oxidative stress. The carriage of Val66Met polymorphism has effects on brain-derived neurotrophic factor secretion and has been associated with the pathophysiology of a variety of neurodegenerative and neuropsychiatric disease. The understanding of how this naturally occurring single nucleotide polymorphism impacts cognition, visual system, and brain structures in relation to aging is an essential first step in associating genetic variations in the neurotrophin system to definable biological outcomes. The purpose of this chapter was to review the recent literature that investigated the interaction between the brain-derived neurotrophic factor Val66Met and aging and established Val66Met’s important role in morphological and functional changes in humans.
Background: This study aimed to discover the association between parameters of event-related potentials (ERPs) and categorization of images of visual scenes, both emotionally-charged and neutral, in carriers of different genotypes of the COMT, HTR2A, BDNF genes.
Methods: Electroencephalogram (EEG) and ERPs were recorded at 128 leads, with two ear referents. Images of different visual scenes were presented to the study participants sequentially on a monitor screen. The participants’ task was to examine these images and indicate what emotions (negative, neutral or positive) they elicit. Comparison of event-related potentials was carried out using unpaired Student t-test in EEGLAB toolbox.
Results: COMT. A stronger reaction, as reflected in the amplitude of the ERPs, in participants with the recessive homozygous Met/Met genotype was observed on latency around 200 ms to the stimuli, assessed as positive. Carriers of dominant homozygous Val/Val genotype had higher amplitude of 200 ms peak when assessed scene images as either neutral or negative in comparison to other genotypes. Participant with the Val/Met heterozygous genotype had higher amplitude of ERP that Met/Met group on same latency when assessed stimuli as negative.
HTR2A . Significant increase in negativity in the parietal-occipital regions revealed in the range of 350-420 ms in participants with the recessive homozygous A/A genotype when choosing any type of assessment, compared to carriers of the heterozygous genotype A/G and the dominant homozygous G/G genotype.
BDNF. Participants with Val/Val genotype categorized the visual images more thoroughly, as reflected in greater activation of the parietal-occipital zones and higher amplitude on ERP peak on 190 ms (negative assessment) and 160 ms (neutral assessment) then Val/Met carriers.
Conclusions: The COMT, HTR2A, BDNF gene different genotypes are associated with the process of categorizing emotionally charged and neutral visual scenes, and this relationship is reflected in the ERP parameters.
Background: This study aimed to discover the association between parameters of event-related potentials (ERPs) and categorization of images of visual scenes, both emotionally-charged and neutral, in carriers of polymorphisms of the COMT, HTR2A, BDNF genes.
Methods: Electroencephalogram (EEG) and ERPs were recorded at 128 leads, with two ear referents. Images of different visual scenes were presented to the study participants sequentially on a monitor screen. The participants’ task was to examine these images and indicate what emotions (negative, neutral or positive) they elicit. Comparison of event-related potentials was carried out using unpaired Student t-test in EEGLAB toolbox.
Results: COMT. A stronger reaction, as reflected in the amplitude of the ERPs, in participants with the recessive homozygous Met/Met genotype was observed on latency around 200 ms to the stimuli, assessed as positive. Carriers of dominant homozygous Val/Val genotype had higher amplitude of 200 ms peak when assessed scene images as either neutral or negative in comparison to other genotypes. Participant with the Val/Met heterozygous genotype had higher amplitude of ERP that Met/Met group on same latency when assessed stimuli as negative.
HTR2A. Significant increase in negativity in the parietal-occipital regions revealed in the range of 350-420 ms in participants with the recessive homozygous A/A genotype when choosing any type of assessment, compared to carriers of the heterozygous genotype A/G and the dominant homozygous G/G genotype.
BDNF. Participants with Val/Val genotype categorized the visual images more thoroughly, as reflected in greater activation of the parietal-occipital zones and higher amplitude on ERP peak on 190 ms (negative assessment) and 160 ms (neutral assessment) then Val/Met carriers.
Conclusions: The COMT, HTR2A, BDNF gene polymorphisms are associated with the process of categorizing emotionally charged and neutral visual scenes, and this relationship is reflected in the ERP parameters.
Susceptibility to interference increases with age but there is large inter-individual variability in interference control in older adults due to a number of biological and environmental factors. The present study aims at analyzing behavior and ERPs in a Stroop interference task with increasing difficulty in a sample of 246 young, middle-aged and healthy old participants. The old age group was divided into three subgroups based on performance scores. The results show a gradual performance reduction with increasing age and task difficulty. However, old high performers reached a performance level comparable to middle-aged subjects. The contingent negative variation (CNV) reflecting preparation and proactive task control and the target-locked P2/N2 complex associated with retrieval and implementation of S-R mappings during reactive task control were larger in the old high than low performers and similar to middle-aged or even young participants. High performance was limited to executive control tasks, while other cognitive functions were less affected. In addition, high performance was associated with higher level of education, usage of foreign languages and higher IQ. Thus, the performance differences in old age were discussed in the framework of cognitive reserve that constitutes individual differences in neural networks underlying task performance.
The Val66Met single nucleotide polymorphism (SNP) has previously been reported to impact performance on recognition memory tasks. Whether the two subprocesses of recognition, familiarity and recollection, are differentially impacted by the Val66Met SNP remains unknown. Using event-related potentials (ERPs) recorded during a source memory task, we attempted to dissociate these two subprocesses. Behaviourally, we used participants' scores on an item-recognition subtask as a measure of familiarity, and participants' scores on a source-recognition subtask as a measure of recollection. Our findings reveal that Val/Val individuals outperform Met allele carriers on the item- but not the source-recognition task. Electrophysiologically, we were interested in the N400, an early frontal component previously linked to familiarity, and the late positive complex (LPC), a posterior component linked to recollection. We found evidence for Val/Val individuals having larger amplitudes of the LPC compared to Met allele carriers, and evidence for no difference in the N400 amplitudes of these groups. Based on the lack of dissociation between familiarity- and recollection-specific ERPs at the LPC time window, we argue that our behavioural and ERP results might reflect better item-recognition for Val/Val individuals compared to Met allele carriers. We further suggest that both these results reflect differences related to familiarity, rather than recollection.
Working memory (WM) training paired with transcranial direct current stimulation (tDCS) can improve executive function in older adults. The unclear mechanism of tDCS likely depends on tDCS intensity, and task relevant genetic factors (e.g., for WM: COMT val¹⁵⁸met, DAT, BDNF val⁶⁶met). Higher tDCS intensity does not always lead to greater cognitive gains, and genetic polymorphisms may modulate tDCS-linked WM improvements. To evaluate these factors, 137 healthy older adults provided DNA samples and received Visual and Spatial WM training paired with tDCS (sham, 1, 1.5, 2 mA). After one session of tDCS, significant group differences in WM performance were predicted by COMT val¹⁵⁸met status. One month after training, there was a significant interaction of tDCS intensity, COMT genotype, and WM task. Specifically, val/val homozygotes benefited most from 1.5 mA tDCS on Visual WM and from 1 mA tDCS on Spatial WM. For met/met homozygotes, 2 mA resulted in significantly poorer performance compared to 1.5 mA on Spatial WM. While this pattern was observed with relatively small sample sizes, these data indicate that variations in COMT val¹⁵⁸met may predict the nature of WM improvement after initial and longitudinal tDCS. This contributes to our understanding of the underlying mechanism by which tDCS affects behaviour.
Unlabelled:
It is hypothesized that a fundamental function of sleep is to restore an individual's day-to-day ability to learn and to constantly adapt to a changing environment through brain plasticity. Brain-derived neurotrophic factor (BDNF) is among the key regulators that shape brain plasticity. However, advancing age and carrying the BDNF Met allele were both identified as factors that potentially reduce BDNF secretion, brain plasticity, and memory. Here, we investigated the moderating role of BDNF polymorphism on sleep and next-morning learning ability in 107 nondemented individuals who were between 55 and 84 years of age. All subjects were tested with 1 night of in-laboratory polysomnography followed by a cognitive evaluation the next morning. We found that in subjects carrying the BDNF Val66Val polymorphism, consolidated sleep was associated with significantly better performance on hippocampus-dependent episodic memory tasks the next morning (β-values from 0.290 to 0.434, p ≤ 0.01). In subjects carrying at least one copy of the BDNF Met allele, a more consolidated sleep was not associated with better memory performance in most memory tests (β-values from -0.309 to -0.392, p values from 0.06 to 0.15). Strikingly, increased sleep consolidation was associated with poorer performance in learning a short story presented verbally in Met allele carriers (β = -0.585, p = 0.005). This study provides new evidence regarding the interacting roles of consolidated sleep and BDNF polymorphism in the ability to learn and stresses the importance of considering BDNF polymorphism when studying how sleep affects cognition.
Significance statement:
Individuals with the BDNF Val/Val (valine allele) polymorphism showed better memory performance after a night of consolidated sleep. However, we observed that middle-aged and older individuals who are carriers of the BDNF Met allele displayed no positive association between sleep quality and their ability to learn the next morning. This interaction between sleep and BDNF polymorphism was more salient for hippocampus-dependent tasks than for other cognitive tasks. Our results support the hypothesis that reduced activity-dependent secretion of BDNF impairs the benefits of sleep on synaptic plasticity and next-day memory. Our work advances the field by revealing new evidence of a clear genetic heterogeneity in how sleep consolidation contributes to the ability to learn.
Hypotheses about the P3 component of the event-related EEG potential have usually assumed that P3b reflects some processing independent from organizing the response. In contrast, the notion that P3b is related to a decision process implies some mediating function between stimulus and response. If P3b does indeed reflect the link between perceptual processing and response preparation (1) amplitudes should be as large in response-locked averages as in stimulus-locked averages, (2) this should be true independent of response speed, for separate subaverages of slow and fast responses, and (3) latencies should vary across response speed both in stimulus-locked and in response-locked averages. These hypotheses were tested in data evoked by visual and auditory stimuli in choice-response tasks. All three predictions were confirmed. In contrast to this balanced relation to perception and responding, fronto-central P3 with auditory stimuli was stimulus-related and, for comparison, the peak amplitudes of both the response-force and of the lateralized readiness potential were response-related. We conclude that P3b reflects a process that mediates between perceptual analysis and response initiation, possibly monitoring whether the decision to classify some stimulus is appropriately transformed into action.
Notes that to understand the endogenous components of the event-related potential (ERP), data about the components' antecedent conditions to form hypotheses about the information-processing function of the underlying brain activity must be used. These hypotheses generate testable predictions about the consequences of the component. The application of this approach to the analysis of the P300 component is reviewed. Certain factors suggest that P300 is a manifestation of activity occurring whenever one's model of the environment must be revised. Tests of 3 predictions based on this "context updating" model are reviewed. Open peer commentary follows. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This paper reviews the literature on the Nl wave of the human auditory evoked potential. It concludes that at least six different cerebral processes can contribute to (he negative wave recorded from the scalp with a peak latency between 50 and 150 ms: a component generated in the auditory-cortex on the supratemporal plane, a component generated in the association cortex on the lateral aspect of the temporal and parietal cortex, a component generated in the motor and premotor cortices, the mismatch negativity, a temporal component of the processing negativity, and a frontal component of the processing negativity, The first three, which can be considered ‘true’ N1 components, are controlled by the physical and temporal aspects of the stimulus and by the general state of the subject. The other three components are not necessarily elicited by a stimulus but depend on the conditions in which the stimulus occurs. They often last much longer than the true N1 components that they overlap.
The temporal context of an acoustic signal can greatly influence its perception. The present study investigated the neural correlates underlying perceptual facilitation by regular temporal contexts in humans. Participants listened to temporally regular (periodic) or temporally irregular (nonperiodic) sequences of tones while performing an intensity discrimination task. Participants performed significantly better on intensity discrimination during periodic than nonperiodic tone sequences. There was greater activation in the putamen for periodic than nonperiodic sequences. Conversely, there was greater activation in bilateral primary and secondary auditory cortices (planum polare and planum temporale) for nonperiodic than periodic sequences. Across individuals, greater putamen activation correlated with lesser auditory cortical activation in both right and left hemispheres. These findings suggest that temporal regularity is detected in the putamen, and that such detection facilitates temporal-lobe cortical processing associated with superior auditory perception. Thus, this study reveals a corticostriatal system associated with contextual facilitation for auditory perception through temporal regularity processing.
Perception of temporal patterns is critical for speech, movement, and music. In the auditory domain, perception of a regular pulse, or beat, within a sequence of temporal intervals is associated with basal ganglia activity. Two alternative accounts of this striatal activity are possible: "searching" for temporal regularity in early stimulus processing stages or "prediction' of the timing of future tones after the beat is found (relying on continuation of an internally generated beat). To resolve between these accounts, we used functional magnetic resonance imaging (fMRI) to investigate different stages of beat perception. Participants heard a series of beat and nonbeat (irregular) monotone sequences. For each sequence, the preceding sequence provided a temporal beat context for the following sequence. Beat sequences were preceded by nonbeat sequences, requiring the beat to be found anew ("beat finding" condition), or by beat sequences with the same beat rate ("beat continuation"), or a different rate ("beat adjustment"). Detection of regularity is highest during beat finding, whereas generation and prediction are highest during beat continuation. We found the greatest striatal activity for beat continuation, less for beat adjustment, and the least for beat finding. Thus, the basal ganglia's response profile suggests a role in beat prediction, not in beat finding.
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin growth factor family and is implicated as a modulator of neuronal survival and differentiation, synaptic plasticity, and higher order cognitive functions such as learning and memory. A common single-nucleotide polymorphism (SNP) has been identified in the human BDNF gene (BDNF Val66Met) that leads to decreased BDNF secretion and impairments in specific forms of learning in humans. To better understand the impact of this SNP on biological function, the authors generated a mouse model containing the BDNF Met allele, which they found to replicate the key phenotypes observed in humans and provided further insight into the functional impact of this SNP in vivo. They used a "bottom-up" approach to study the BDNF SNP, which provided external validation in biologically less complex, genetically uniform systems, which minimized the variability inherent in human studies. In this review, the authors discuss the impact of the BDNF SNP on learning and memory while providing arguments for the relevance of a vertically integrated approach to studying human genetic variants.
Technological advances and a greater degree of inter-laboratory co-operation mean that genome-wide analyses can now be used to identify genetic variants that are robustly associated with the risk of developing psychiatric and neurological disorders. In contrast to the candidate gene approach, such screens may identify variants within genes which have a hitherto unappreciated role in disorder pathogenesis, and whose brain function is obscure. In this Perspective, I discuss how the behavioral functions of such genes may be investigated using model systems, drawing attention to the potential caveats and limitations with such approaches. The power of focused cross-species studies needs to be effectively exploited to enable useful insights into the molecular pathogenesis of common and disabling disorders, and ultimately to provide better clinical outcomes for patients.
In this study we examined the relevance of the functional brain-derived neurotrophic factor (BDNF) Val66Met polymorphism as a modulator of task-switching performance in healthy elderly by using behavioral and event-related potential (ERP) measures. Task switching was examined in a cue-based and a memory-based paradigm. Val/Val carriers were generally slower, showed enhanced reaction time variability and higher error rates, particularly during memory-based task switching than the Met-allele individuals. On a neurophysiological level these dissociative effects were reflected by variations in the N2 and P3 ERP components. The task switch-related N2 was increased while the P3 was decreased in Met-allele carriers, while the Val/Val genotype group revealed the opposite pattern of results. In cue-based task-switching no behavioral and ERP differences were seen between the genotypes. These data suggest that superior memory-based task-switching performance in elderly Met-allele carriers may emerge due to more efficient response selection processes. The results implicate that under special circumstances the Met-allele renders cognitive processes more efficient than the Val/Val genotype in healthy elderly, corroborating recent findings in young subjects.
Behavioral adaptation depends on the recognition of response errors and processing of this error-information. Error processing is a specific cognitive function crucial for behavioral adaptation. Neurophysiologically, these processes are reflected by an event-related potential (ERP), the error negativity (Ne/ERN). Even though synchronization processes are important in information processing, its role and neurobiological foundation in behavioral adaptation are not understood. The brain-derived neurotrophic factor (BDNF) strongly modulates the establishment of neural connectivity that determines neural network dynamics and synchronization properties. Therefore altered synchronization processes may constitute a mechanism via which BDNF affects processes of error-induced behavioral adaptation. We investigate how variants of the BDNF gene regulate EEG-synchronization processes underlying error processing. Subjects (n=65) were genotyped for the functional BDNF Val66Met polymorphism (rs6265). We show that Val/Val genotype is associated with stronger error-specific phase-locking, compared with Met allele carriers. Posterror behavioral adaptation seems to be strongly dependent on these phase-locking processes and efficacy of EEG-phase-locking-behavioral coupling was genotype dependent. After correct responses, neurophysiological processes were not modulated by the polymorphism, underlining that BDNF becomes especially necessary in situations requiring behavioral adaptation. The results suggest that alterations in neural synchronization processes modulated by the genetic variants of BDNF Val66Met may be the mechanism by which cognitive functions are affected.
A specific polymorphism of the brain-derived neurotrophic factor (BDNF) gene is associated with alterations in brain anatomy and memory; its relevance to the functional connectivity of brain networks, however, is unclear. Given that altered hippocampal function and structure has been found in adults who carry the methionine (met) allele of the BDNF gene and the molecular studies elucidating the role of BDNF in neurogenesis and synapse formation, we examined the association between BDNF gene variants and neural resting connectivity in children and adolescents. We observed a reduction in hippocampal and parahippocampal to cortical connectivity in met-allele carriers within both default-mode and executive networks. In contrast, we observed increased connectivity to amygdala, insula and striatal regions in met-carriers, within the paralimbic network. Because of the known association between the BDNF gene and neuropsychiatric disorder, this latter finding of greater connectivity in circuits important for emotion processing may indicate a new neural mechanism through which these gene-related psychiatric differences are manifest. Here we show that the BDNF gene, known to regulate synaptic plasticity and connectivity in the brain, affects functional connectivity at the neural systems level. In addition, we demonstrate that the spatial topography of multiple high-level resting state networks in healthy children and adolescents is similar to that observed in adults.
Hypotheses about the P3 component of the event-related EEG potential have usually assumed that P3b reflects some processing independent from organizing the response. In contrast, the notion that P3b is related to a decision process implies some mediating function between stimulus and response. If P3b does indeed reflect the link between perceptual processing and response preparation (1) amplitudes should be as large in response-locked averages as in stimulus-locked averages, (2) this should be true independent of response speed, for separate subaverages of slow and fast responses, and (3) latencies should vary across response speed both in stimulus-locked and in response-locked averages. These hypotheses were tested in data evoked by visual and auditory stimuli in choice-response tasks. All three predictions were confirmed. In contrast to this balanced relation to perception and responding, fronto-central P3 with auditory stimuli was stimulus-related and, for comparison, the peak amplitudes of both the response-force and of the lateralized readiness potential were response-related. We conclude that P3b reflects a process that mediates between perceptual analysis and response initiation, possibly monitoring whether the decision to classify some stimulus is appropriately transformed into action.
Brain-derived neurotrophic factor (BDNF) plays an important role in neuroplasticity and promotes axonal growth, but its secretion, regulated by a BDNF gene, declines with age. The low-activity (met) allele of common polymorphism BDNF val66met is associated with reduced production of BDNF. We examined whether age-related reduction in the integrity of cerebral white matter (WM) depends on the BDNF val66met genotype. Forty-one middle-aged and older adults participated in the study. Regional WM integrity was assessed by fractional anisotropy (FA) computed from manually drawn regions of interest in the genu and splenium of the corpus callosum on diffusion tensor imaging scans. After controlling for effects of sex and hypertension, we found that only the BDNF 66met carriers displayed age-related declines in the splenium FA, whereas no age-related declines were shown by BDNF val homozygotes. No genotype-related differences were observed in the genu of the corpus callosum. This finding is consistent with a view that genetic risk for reduced BDNF affects posterior regions that otherwise are considered relatively insensitive to normal aging. Those individuals with a genetic predisposition for decreased BDNF expression may not be able to fully benefit from BDNF-based plasticity and repair mechanisms.
Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words)
Cognitive functions are thought to deteriorate globally in late stages of various neurodegenerative disorders. Here we describe that this general assumption is not justified and fails in Huntington's disease (HD). Presymptomatic gene mutation carriers (pHDs) and healthy controls performed worse compared with symptomatic HDs in an auditory signal detection task. During task performance, behavioral data and event-related potentials (ERPs) [i.e., MMN (mismatch negativity), P3a, and RON (reorienting negativity)] were recorded. Not only behavioral performance but also neurophysiological correlates of auditory sensory memory and attentional reorientation indicate enhanced performance occurring primal in late stages of a neurodegenerative disorder. Increased activity of the NMDA-receptor system, an assumed pathogenic mechanism in HD, might facilitate signal propagation at striatal level that enables more efficient task execution through a winner-take-all process. The results challenge the view that late stage neurodegeneration is necessarily related to a global decline in cognitive abilities in HD. In contrast, selectively enhanced cognitive functioning can emerge together with otherwise impaired cognitive functioning.
Levodopa induced dyskinesias (LID) are a common problem which ultimately limit the effective treatment of patients with Parkinson's disease (PD). There is accumulating evidence that LID develop due to abnormal synaptic plasticity, which is in turn influenced by the release of brain derived neurotrophic factor (BDNF).
The influence of a common functional polymorphism of the BDNF gene on the risk of developing dyskinesias in a large cohort of patients with PD (n = 315), who were independently and variably treated with levodopa and/or other dopaminergic treatments, was investigated.
Patients with the met allele of BDNF, associated with lower activity dependent secretion of BDNF, were at significantly higher risk of developing dyskinesias earlier in the course of treatment with dopaminergic agents (hazard ratio for each additional met allele 2.12, p = 0.001), which persisted following adjustment for potential confounding variables.
This functional polymorphism may help predict which individuals are most at risk of LID and is consistent with the known actions of BDNF on synaptic plasticity in the striatum.
Genetic variability in the dopaminergic and neurotrophic systems could contribute to age-related impairments in executive control and memory function. In this study we examined whether genetic polymorphisms for catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) were related to the trajectory of cognitive decline occurring over a 10-year period in older adults. A single nucleotide polymorphism in the COMT (Val158/108Met) gene affects the concentration of dopamine in the prefrontal cortex. In addition, a Val/Met substitution in the pro-domain for BDNF (Val66Met) affects the regulated secretion and trafficking of BDNF with Met carriers showing reduced secretion and poorer cognitive function. We found that impairments over the 10-year span on a task-switching paradigm did not vary as a function of the COMT polymorphism. However, for the BDNF polymorphism the Met carriers performed worse than Val homozygotes at the first testing session but only the Val homozygotes demonstrated a significant reduction in performance over the 10-year span. Our results argue that the COMT polymorphism does not affect the trajectory of age-related executive control decline, whereas the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age.
Intracranial event-related potentials (ERPs) were recorded in neurological patients to infrequent higher-pitch 'deviant' tones and to frequent 'standard' tones when they occurred, in random order in a mixed sequence of standard and deviant tones and when they occurred in separate sequences, that is, infrequent tones alone with intervals similar to inter-deviant intervals of the mixed sequence and frequent tones alone with intervals similar to those between the standard tones of the mixed sequence. When the tones were ignored, ERPs showed three types of responses revealing three different processes involved in stimulus discrimination in the superior temporal cortex: (1) a pitch-dependent response in the primary auditory cortex; (2) an interstimulus-interval dependent response in the secondary auditory cortex; and (3) a change-detection ('mismatch') response in the auditory association cortex. When the tones were attended, ERPs to deviant and standard tones showed differences also in the basal ganglia-thalamic circuits and in the hippocampus, indicating their involvement in attentive processing of auditory stimulus changes.
This article reviews recent event-related brain potential (ERP) studies of involuntary attention and distractibility in response to novelty and change in the acoustic environment. These studies show that the mismatch negativity, N(1) and P(3a) ERP components elicited by deviant or novel sounds in an unattended sequence of repetitive stimuli index different processes along the course to involuntary attention switch to distracting stimuli. These studies used new auditory-auditory and auditory-visual distraction paradigms, which enable one to assess objectively abnormal distractibility in several clinical patient groups, such as those suffering from closed-head injuries or chronic alcoholism.
Modeling of the basal ganglia has played a major role in our understanding of this elusive group of nuclei. Models of the basal ganglia have undergone evolutionary and revolutionary changes over the last 20 years, as new research in the fields of anatomy, physiology and biochemistry of these nuclei has yielded new information. Early models dealt with a single pathway through the nuclei and focused on the nature of the processing performed within it, convergence of information versus parallel processing of information. Later, the Albin-DeLong "box-and-arrow" model characterized the inter-nuclei interaction as multiple pathways while maintaining a simplistic scalar representation of the nuclei themselves. This model made a breakthrough by providing key insights into the behavior of these nuclei in hypo- and hyper-kinetic movement disorders. The next generation of models elaborated the intra-nuclei interactions and focused on the role of the basal ganglia in action selection and sequence generation which form the most current consensus regarding basal ganglia function in both normal and pathological conditions. However, new findings challenge these models and point to a different neural network approach to information processing in the basal ganglia. Here, we take an in-depth look at the reinforcement driven dimensionality reduction (RDDR) model which postulates that the basal ganglia compress cortical information according to a reinforcement signal using optimal extraction methods. The model provides new insights and experimental predictions on the computational capacity of the basal ganglia and their role in health and disease.
Abstract Involuntary switching to task-irrelevant sound change was studied by measuring event-related brain potentials (ERPs) and behavioral performance in a dichotic listening paradigm. Pairs of tones (S1 and S2) were presented and subjects were instructed to ignore S1 (delivered to the left ear) and to make a go/no-go response to the subsequent S2 (delivered to the right ear). On most trials, the task-irrelevant S1 was of standard frequency, but occasionally it deviated from the standard frequency either by a small or large amount. It was predicted that deviant stimuli were automatically detected and that they could involuntarily capture attention. If they lead to attention switching, less capacity should be available for the processing of target tones resulting in impaired processing of S2. As in many previous studies, deviant tones elicited the mismatch negativity (MMN), which is a component of the ERP indicating automatic change detection. Furthermore, targets preceded by a deviant tone elicited a smaller N1 wave and were detected less effectively than targets preceded by a standard tone. This impaired processing of targets following task-irrelevant changes occurred only with short S1-S2 intervals (Experiment I) but not with long ones (Experiment II). The results support a model claiming that the auditory system possesses a change detection system that monitors the acoustic input and may produce an attentional "interrupt" signal when a deviant occurs. The involuntary attentional capture caused by this signal leads to impoverished processing of closely succeeding stimuli.
P3 is the most prominent of the electrical potentials of the human electroencephalogram that are sensitive to psychological variables. According to the most influential current hypothesis about its psychological significance [E. Donchin's], the “context updating” hypothesis, P3 reflects the updating of working memory. This hypothesis cannot account for relevant portions of the available evidence and it entails some basic contradictions. A more general formulation of this hypothesis is that P3 reflects the updating of expectancies. This version implies that P3-evoking stimuli are initially unexpected but later become expected. This contradiction cannot be resolved within this formulation. The alternative “context closure” hypothesis retains the concept of “strategic information processing” emphasized by the context updating hypothesis. P3s are evoked by events that are awaited when subjects deal with repetitive, highly structured tasks; P3s arise from subjects' combining successive stimuli into larger units. The tasks in which P3s are elicited can accordingly be classified in terms of their respective formal sequences of stimuli. P3 may be a physiological indicator of excess activation being released from perceptual control areas.
The ADORA2A gene encodes the adenosine A(2A) receptor that is highly expressed in the striatum where it plays a role in modulating glutamatergic and dopaminergic transmission. Glutamatergic signaling has been suggested to play a pivotal role in cognitive functions related to the pre-attentive processing of external stimuli. Yet, the precise molecular mechanism of these processes is poorly understood. Therefore, we aimed to investigate whether ADORA2A gene variation has modulating effects on visual pre-attentive sensory memory processing. Studying two polymorphisms, rs5751876 and rs2298383, in 199 healthy control subjects who performed a partial-report paradigm, we find that ADORA2A variation is associated with differences in the efficiency of pre-attentive sensory memory sub-processes. We show that especially the initial visual availability of stimulus information is rendered more efficiently in the homozygous rare genotype groups. Processes related to the transfer of information into working memory and the duration of visual sensory (iconic) memory are compromised in the homozygous rare genotype groups. Our results show a differential genotype-dependent modulation of pre-attentive sensory memory sub-processes. Hence, we assume that this modulation may be due to differential effects of increased adenosine A(2A) receptor signaling on glutamatergic transmission and striatal medium spiny neuron (MSN) interaction.
The developing nervous system is particularly vulnerable to chemical insults. Exposure to chemicals can result in neurobehavioural alterations, and these have been used as sensitive readouts to assess neurotoxicity in animals and man. Deconstructing neurobehaviour into relevant cellular and molecular components may allow for detection of specific neurotoxic effects in cell-based systems, which in turn may allow an easier examination of neurotoxic pathways and modes of actions and eventually inform the regulatory assessment of chemicals with potential developmental neurotoxicity. Here, current developments towards these goals are reviewed. Imaging genetics (CB) provides new insights into the neurobiological correlates of cognitive function that are being used to delineate neurotoxic mechanisms. The gaps between in vivo neurobehaviour and real-time in vitro measurements of neuronal function are being bridged by ex vivo measurements of synaptic plasticity (RW). An example of solvent neurotoxicity demonstrates how an in vivo neurological defect can be linked via the N-methyl-d-aspartate (NMDA)-glutamate receptor as a common target to in vitro readouts (AB). Axonal and dendritic morphology in vitro proved to be good correlates of neuronal connectivity and neurobehaviour in animals exposed to polychlorinated biphenyls and organophosphorus pesticides (PJL). Similarly, chemically induced changes in neuronal morphology affected the formation of neuronal networks on structured surfaces. Such network formation may become an important readout for developmental neurotoxicity in vitro (CvT), especially when combined with human neurons derived from embryonic stem cells (ML). We envision that future in vitro test systems for developmental neurotoxicity will combine the above approaches with exposure information, and we suggest a strategy for test system development and cell-based risk assessment.
The Val66Met, G196A (rs6265) polymorphism in the brain-derived neurotrophic factor gene, BDNF, located at 11p13, has been associated with a wide range of cognitive functions. Yet, the pattern of results is complex and conflicting. In this study, we conducted a meta-analysis that included 23 publications containing 31 independent samples comprised of 7095 individuals. The phenotypes that were examined in this analysis covered a wide variety of cognitive functions and included indicators of general cognitive ability, memory, executive function, visual processing skills and cognitive fluency. The meta-analysis did not establish significant genetic associations between the Val66Met polymorphism and any of the phenotypes that were included.
Numerous studies suggested an age-related decline in speech perception under difficult listening conditions. Here, spoken language understanding of two age groups of listeners was investigated in a naturalistic "stock price monitoring" task. Stock prices of listed companies were simultaneously recited by three speakers at different positions in space and presented via headphones to 14 younger and 14 older listeners (age ranges 19-25 and 54-64 years, respectively). The listeners had to respond when prices of target companies exceeded a specific value, but to ignore all other prices as well as beep sounds randomly interspersed within the stock prices. Older listeners did not produce more missing responses, or longer response times than younger listeners. However, differences in event-related potentials indicated a reduced parietal P3b of older, relative to younger, listeners. Separate analyses for those listeners who performed relatively high or low in the behavioral task revealed a right-frontal P3a that was pronounced especially in the group of high-performing older listeners. Correlational analyses indicated a direct relationship between P3a amplitude and spoken language comprehension in older, but not younger, listeners. Furthermore, younger (especially, low-performing) listeners showed a more pronounced P2 on irrelevant beep sounds than older listeners. These subtle differences in cortical processing between age groups suggest that high performance of older middle-aged listeners in demanding listening situations is associated with increased engagement of frontal brain areas, and thus the allocation of mental resources for compensation of potential declines in spoken language understanding.
Physiological aging affects early sensory-perceptual processes. The aim of this experiment was to evaluate changes in auditory sensory memory in physiological aging using the Mismatch Negativity (MMN) paradigm as index. The MMN is a marker recorded through the electroencephalogram and is used to evaluate the integrity of the memory system. We adopted a new, faster paradigm to look for differences between 3 groups of subjects of different ages (young, middle age and older adults) as a function of short or long intervals between stimuli. We found that older adults did not show MMN at long interval condition and that the duration of MMN varied according to the participants' age. The current study provides electrophysiological evidence supporting the theory that the encoding of stimuli is preserved during normal aging, whereas the maintenance of sensory memory is impaired. Considering the advantage offered by the MMN paradigm used here, these data might be a useful reference point for the assessment of auditory sensory memory in pathological aging (e.g., in neurodegenerative diseases).
The brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is involved in nerve growth and survival. Especially, a single nucleotide polymorphism (SNP) in the BDNF gene, Val66Met, has gained a lot of attention, because of its effect on activity-dependent BDNF secretion and its link to impaired memory processes. We hypothesize that the BDNF Val66Met polymorphism may have modulatory effects on the visual sensory (iconic) memory performance. Two hundred and eleven healthy German students (106 female and 105 male) were included in the data analysis. Since BDNF is also discussed to be involved in the pathogenesis of depression, we additionally tested for possible interactions with depressive mood. The BDNF Val66Met polymorphism significantly influenced iconic-memory performance, with the combined Val/Met-Met/Met genotype group revealing less time stability of information stored in iconic memory than the Val/Val group. Furthermore, this stability was positively correlated with depressive mood exclusively in the Val/Val genotype group. Thus, these results show that the BDNF Val66Met polymorphism has an effect on pre-attentive visual sensory memory processes.
J. Neurochem. (2010) 113, 1073–1091.
Abnormal expansion of a polyglutamine tract in huntingtin (Htt) protein results in Huntington’s disease (HD), an autosomal dominant neurodegenerative disorder involving progressive loss of motor and cognitive function. Contrasting with the ubiquitous tissue expression of polyglutamine-expanded Htt, HD pathology is characterized by the increased vulnerability of specific neuronal populations within the striatum and the cerebral cortex. Morphological, biochemical, and functional characteristics of neurons affected in HD that might render these cells more vulnerable to the toxic effects of polyglutamine-Htt are covered in this review. The differential vulnerability of neurons observed in HD is discussed in the context of various major pathogenic mechanisms proposed to date, and in line with evidence showing a ‘dying-back’ pattern of degeneration in affected neuronal populations.
Response inhibition is a basic executive function which is dysfunctional in various basal ganglia diseases. The brain-derived-neurotrophic-factor (BDNF) plays an important pathophysiological role in these diseases. In the current study we examined the functional relevance of the BDNF val66met polymorphism for response inhibition processes in 57 healthy human subjects using event-related potentials (ERPs), i.e. the Nogo-N2 and Nogo-P3, which likely reflect different aspects of inhibition. Our results support the pre-motor inhibition theory of the Nogo-N2. We show that the BDNF val66met polymorphism selectively modulates the Nogo-N2. Response inhibition was better in the val/met-met/met group, since this group committed fewer false alarms, and their Nogo-N2 was larger, compared to the val/val group. This is the first study showing that met alleles of the BDNF val66met polymorphism confer an advantage for a specific cognitive function. We propose a neuronal model how this advantage gets manifest on a neuronal level.
Recently, a genome-wide single nucleotide polymorphism association study has identified a sequence variant 30 kb upstream of the c-Myc gene (allele T of rs9642880) that confers susceptibility to bladder cancer. However, the role of exposure to bladder carcinogens has not been considered. This prompted us to analyse the relevance of this polymorphism in 515 bladder cancer cases and 893 controls where the quality and quantity of occupational exposure to bladder carcinogens has been documented. When we analysed a hospital-based case-control series not selected for occupational exposure, rs9642880[T] was influential, in contrast to GSTM1 0/0. However, in a case-control series of patients that have been occupationally exposed to aromatic amines and polycyclic aromatic hydrocarbons, rs9642880[T] was not influential but GSTM1 0/0 was significantly associated with bladder cancer risk. Therefore, the degree to which rs9642880[T] and GSTM1 0/0 confer susceptibility to urinary bladder cancer seems to depend on the extent of exposure to urinary bladder carcinogens.
Response inhibition is a component of executive functions, which can be divided into distinct subprocesses by means of event-related potentials (ERPs). These subprocesses are (pre)-motor inhibition and inhibition monitoring, which are probably reflected by the Nogo-N2 and Nogo-P3, respectively. Here we ask, if these subprocesses may depend on distinct basal ganglia subsystems. We examined response inhibition processes in an extended sample of young and elderly subjects, patients with Parkinson's disease (PD) and Huntington' disease (HD). This combination of groups also allow us to study whether, and to what degree, pathological basal ganglia changes and healthy aging have similar and/or different effects on these processes. We show that subprocesses of response inhibition are differentially modulated by distinct basal ganglia circuits. Processes related to (pre)-motor inhibition appear to be modulated by the nigrostriatal system, and are sensitive to aging and age-related basal ganglia diseases (i.e. PD). Parkinson's disease induces additive effects of aging and pathology. In contrast, inhibition monitoring is most likely modulated by the mesocortico-limbic dopamine system. These processes are equally affected in healthy aging and both basal ganglia diseases (i.e. PD, HD).
Glutamate's role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis, and neuron survival in the developing and adult mammalian nervous system. Cell-surface glutamate receptors are coupled to Ca(2+) influx and release from endoplasmic reticulum stores, which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF), which, in turn, modifies neuronal glutamate sensitivity, Ca(2+) homeostasis, and plasticity. Neurotrophic factors may modify glutamate signaling directly, by changing the expression of glutamate receptor subunits and Ca(2+)-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins, and antiapoptotic Bcl-2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer's disease to psychiatric disorders. By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.
The brain-derived neurotrophic factor (BDNF) gene has become a candidate gene for molecular-genetic studies of mood disorders and schizophrenia, and also for pharmacogenomics of drugs used in the treatment of these conditions, such as mood-stabilizers in bipolar mood disorder, antidepressants in depression, and antipsychotics in schizophrenia. It has been demonstrated that the functional Val66Met polymorphism of the gene can be associated with a number of clinical and pharmacological phenomena in these illnesses.
In this study, we examined whether the Met allele of the BDNF Val66Met polymorphism is associated with selective disruptions to task-relevant information processing. In 475 non-clinical participants for whom BDNF genotype status was determined we used the 'IntegNeuro' computerized battery of neuropsychological tests to assess cognitive performance, an auditory oddball task to elicit the P300 event-related potential (ERP) and, in smaller subsets of these subjects, high resolution structural MRI imaging to quantify fronto-hippocampal grey matter (n=161), and functional magnetic resonance imaging to assess fronto-hippocampal BOLD activation (n=37). Met/Met (MM) homozygotes had higher verbal recall errors, in the absence of differences in attention, executive function, verbal ability or sensori-motor function. Further, MM homozygotes demonstrated a slowed P300 ERP during the oddball task, with corresponding alterations in hippocampal and lateral prefrontal activation, and a localized reduction in hippocampal grey matter. These results are consistent with a subtle impact of the Met allele on fronto-hippocampal systems involved in selective information processing of stimulus context and memory updating within the normal population. The findings also indicate that heritable endophenotypes such as the P300 have value in elucidating genotype-phenotype relationships.
The aim of this study was to investigate aging effects on non-attended changes of auditory stimulation, by using psychophysiological methods. Event-related potentials (ERPs) were recorded to frequent (standard; 950 Hz, p = 0.9) and infrequent (deviant; 1045 Hz, p = 0.1) auditory stimuli in older (mean age = 60.8 years) and younger (mean age = 21.3 years) subjects. In various blocks the inter-stimulus interval (ISI) was either 800, 2400 or 7200 ms. During the experimental sessions the subjects read books, and ignored the auditory stimuli. As a function of ISI, the amplitude of the N1 and the amplitude and latency of the P2 increased. The P2 amplitude was larger in the younger group. In the 120-180 ms latency range the deviant stimuli elicited more negative ERPs (mismatch negativity, MMN) than the standard stimuli. The amplitude of the MMN did not change as a function of ISI. MMN was larger in the younger group. Thus the younger subjects were more sensitive to the deviant stimuli. In the younger group, at the two shorter ISIs, the MMN was followed by a positive wave (P3a). The emergence of this component is an indication of the increased activity of the orienting system in the younger subjects, in comparison to the older age group.
The P300 (P3) event-related potential was obtained from 100 undergraduates with a 2-tone auditory discrimination task (20% targets) and replicated trial block procedure. Normal variation for P3 amplitude and latency was assessed with frequency distributions and descriptive statistics for the midline electrode placements. P3 latency and amplitude were negatively correlated, most strongly at the Pz electrode site. No significant effects between trial block replications, subject gender, or reported alcohol consumption on either amplitude or latency were found.
In order to develop an experimental paradigm for clinical application of cognitive event-related potentials we have recorded these potentials in a group of 27 healthy Japanese, aged 20-78 years, using all 4 stimulus/response combinations of auditory or somatosensory stimuli requiring a counting or button-press response. In an oddball paradigm we recorded N1 and P2 components to frequent auditory stimuli and P100, N150 and P200 components to frequent somatosensory stimuli. These components were also observed in the target responses for their respective modalities together with N2, P270, P3 and slow-wave components. P3 latency increased linearly with age for all 4 experimental conditions, although this increase was not statistically significant for the somatosensory stimulus/button-press response combination. The latency of P270 also increased significantly with age for the auditory stimulus/button-press response combination but did not do so in either of the counting response conditions. The principal difference between the latencies of ERPs to auditory compared with somatosensory stimuli was that P3 was significantly longer for somatosensory stimulation, although differences in task difficulty may have influenced this finding. With regard to amplitude, N2, P3 and slow-wave were all significantly more positive for somatosensory compared with auditory stimulation. The topography of P3 evoked by somatosensory stimuli was most predominant at central electrodes, whereas the auditory P3 was larger parietally. The button-press response was associated with potentials which were smaller in amplitude and shorter in latency than those associated with the count response. The button-press response had a marked effect on the amplitude of P3 recorded at the vertex and the central electrode contralateral to the moving finger.
The topography of auditory event-related potentials (ERPs) was examined during 3 kinds of tasks: selection of a specified real word or nonsense syllable from a list; simple detection of each of the same stimuli without discrimination; and classification of a set of words according to a specified semantic category. The potentials that were associated with the additional processing required by the discriminative tasks were disclosed by subtracting the wave forms obtained in the detection condition from those obtained during discriminative performance. Difference wave forms were also derived between the semantic classification and verbal discriminative ERP to delineate the changes associated with the extraction of word meaning. The topography of the ERP associated with stimulus detection was comparable to that found in previous studies of evoked potentials to non-speech stimuli. This distribution was consistent with 2 cortical generators, one within the supratemporal plane and the other on the lateral surface of the superior temporal gyrus. When discriminative performance was required on the basis of acoustic stimulus properties, the topography of the difference wave form that reflected this discriminative processing extended more posteriorly over temporal cortex. Semantic processing elicited a further posterior extension of ERP components by 330 msec after stimulus onset, as well as longer latency potentials that were not present in the verbal selection task. These differences imply that a more extensive portion of language cortex is engaged in semantic classification than in verbal identification.
A new off-line procedure for dealing with ocular artifacts in ERP recording is described. The procedure (EMCP) uses EOG and EEG records for individual trials in an experimental session to estimate a propagation factor which describes the relationship between the EOG and EEG traces. The propagation factor is computed after stimulus-linked variability in both traces has been removed. Different propagation factors are computed for blinks and eye movements. Tests are presented which demonstrate the validity and reliability of the procedure. ERPs derived from trials corrected by EMCP are more similar to a 'true' ERP than are ERPs derived from either uncorrected or randomly corrected trials. The procedure also reduces the difference between ERPs which are based on trials with different degrees of EOG variance. Furthermore, variability at each time point, across trials, is reduced following correction. The propagation factor decreases from frontal to parietal electrodes, and is larger for saccades than blinks. It is more consistent within experimental sessions than between sessions. The major advantage of the procedure is that it permits retention of all trials in an ERP experiment, irrespective of ocular artifact. Thus, studies of populations characterized by a high degree of artifact, and those requiring eye movements as part of the experimental task, are made possible. Furthermore, there is no need to require subjects to restrict eye movement activity. In comparison to procedures suggested by others, EMCP also has the advantage that separate correction factors are computed for blinks and movements and that these factors are based on data from the experimental session itself rather than from a separate calibration session.
The averaged evoked potential to brief tones was compared for 10 young and 10 elderly female subjects. The amplitudes of the sensory components (P1, N1 and P2) were not affected by an infrequent change in pitch of the tones or instructing subjects to count or ignore them; but overall the elderly had a larger P1 and smaller P2 amplitude and a difference in the scalp distribution of P2. Repetition of the tones produced a decrement in these sensory components and a differential one for young and old subjects A slow potential complex consisting of components N2, P3 and SW appeared to changes in tone pitch and became more pronounced when attention was directed to the tones. Overall smaller SPs for oder subjects were interpreted as evidence for a change with age in the cortical representation of the orienting response. Topographical analysis of SPs indicated diminished activity in frontal (Fz) electrodes for elderly persons, suggestive of an enhanced aging process in the frontal cortices.
The effects of choice complexity on different subcomponents of the late positive complex were investigated. In a previous choice reaction study, two subcomponents of this complex were identified, called P-SR and P-CR, which seem to be related to stimulus evaluation and response selection, respectively. The present study attempts to show the dependence of the P-CR (and the independence of the P-SR) on response selection by manipulating response selection complexity. This was done by having the subjects perform either 2-way or 4-way choice reactions to single letter stimuli. To enhance the discriminability of P-SR and P-CR, visual and auditory stimuli were used, since the P-SR is modality-dependent. Moreover, the stimulus modalities were mixed ("divided attention paradigm"), which was expected to lead to a dissociation of P-SR and P-CR, especially after auditory stimuli. The choice reaction times were about 100 msec longer for difficult than for easy choices. The main ERP result was a 65 msec increase of the P-CR latency for the difficult as compared to the easy choice, while the P-SR latency remained constant. The P-CR latency difference precisely matched the onset difference of the lateralized readiness potential. The P-SR showed a modality-dependent latency and topography, while the P-CR did not. The present data confirm the close relation of one subcomponent of the late positive complex, the P-CR, to the cognitive response-selection process.
Event-related brain potentials (ERPs) were recorded from young, middle-aged, and older adults to infrequent target and novel stimuli during a version of the oddball paradigm. Analyses of scalp distribution suggested that the shift to a more frontally oriented topography with increasing age was confined to the P3 component (as compared to N1 and P2) elicited by both target and novel stimuli. This first demonstration of an age-related shift in the scalp distribution of the novelty P3 elicited by auditory stimuli was associated with an age-related increase in the false-alarm rate to novel stimuli. These age-associated differences in scalp distribution and false-alarm rate are consistent with a change in frontal lobe activity with increasing age.
The conscious perception of infrequent deviant sounds occurring in a series of frequent standard sounds may in part be based on the output of an obligatorily operating deviance detection system. This system encodes invariances inherent to the recent auditory stimulation into short-lived representations of auditory sensory memory and compares each actual input with these representations. The underlying processes may be regarded as preattentive in the sense that they do not rely on the explicit intention of a person to detect deviants and that they may be active even in the absence of attention (although they may be prone to attentional modulations). The output of this feature-specific preattentive deviance detection system fuses into an integrated mismatch signal that in turn may activate subsequent processes that result in the triggering of a motor response.
Advancing age is associated with declines in motor function; understanding age-related changes in the basal ganglia, therefore, is imperative for comprehension of such functional changes. The purpose of this study was to examine the age, sex, and hemispheric differences in volume of the caudate nucleus, the putamen, and the globus pallidus.
In a sample of 148 healthy right-handed adults (18-77 years old) with no evidence of age-related motor disorders, we estimated the volume of the head of the caudate nucleus, the putamen, and the globus pallidus from MR images.
The analyses revealed bilateral age-related shrinkage of the head of the caudate nucleus and the putamen in both sexes. In men, the age-related shrinkage of the caudate was stronger on the left, whereas, in women, the opposite trend was evident. In both sexes, age-related shrinkage of the right putamen was greater than of its left counterpart. The mild bilateral age-related shrinkage of the globus pallidus was observed only in men. In both sexes, we observed significant rightward asymmetry in the putamen, significant leftward asymmetry in the caudate, and no asymmetry in the globus pallidus.
Bilateral age-related shrinkage of the neostriatum is found in healthy adults. The shrinkage of the globus pallidus is less pronounced and may be restricted to men only.
We investigated event-related potential indications for the orienting towards task-irrelevant, distracting aspects of stimulation and for the subsequent reorienting towards task-related aspects of stimulation. An identical experimental protocol was run in three conditions manipulating the task relevance of the sounds. As to be expected, distractors elicited the MMN (reflecting the brain's pre-attentive change detection) in each condition (even when the sounds were ignored) and subsequent N2b and P3 (reflecting orienting towards the distractor) when the sounds were attended. A late negativity was confined to a condition in which subjects discriminating long from short sounds were distracted by task-irrelevant frequency deviations. The 'reorienting negativity' (RON) probably reflects processes in the context of reorienting towards task-relevant aspects of stimulation following distraction.
Responses to glutamate receptor agonists were recorded from identified relay neurons in the dorsal lateral geniculate nucleus of the rat, using the nystatin-perforated patch-clamp technique. Rapid application of glutamate, N-methyl-D-aspartate, (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and kainate induced inward currents at a holding potential of -44 mV. The responses to low concentrations of each agonist were composed only of steady-state currents, but the responses to high concentrations were additionally composed of a rapid transient peak component except in the kainate-induced current. The currents induced by 10(-3)M N-methyl-D-aspartate in the external solution containing 0 mM Mg2+ and 10(-6)M glycine were reduced in amplitude when the external solution contained 1 mM Mg2+, and were abolished when the solution contained no glycine. The currents induced by a neurotransmitter candidate at retinogeniculate synapses, N-acetyl-aspartyl-glutamate, were markedly reduced in amplitude when the solution contained 1 mM Mg2+ or 10(-4)M DL-2-amino-5-phosphonovaleric acid. The current abolished in the Mg2+-containing, glycine-free solution (N-methyl-D-aspartate component) and the current remaining in the same solution (non-N-methyl-D-aspartate component) of the N-acetyl-aspartyl-glutamate response were both increased in a concentration-dependent manner, as the N-acetyl-aspartyl-glutamate concentration was increased. The current-voltage relationship of the currents induced by N-methyl-D-aspartate and N-acetyl-aspartyl-glutamate was characterized by Mg2+-dependent block at hyperpolarized potentials. The inward currents induced by 3 x 10(-4)M AMPA and 3 x 10(-4)M glutamate were markedly potentiated by 10(-4)M cyclothiazide, but the currents induced by 3 x 10(-4)M kainate and 10(-3)M N-acetyl-aspartyl-glutamate (non-N-methyl-D-aspartate component) were little affected. The currents induced by any agonist were not affected by 3 x 10(-4)g/ml concanavalin A. The current induced by 10(-4)M kainate was markedly suppressed by pretreatment with 10(-4)M AMPA or 10(-4)M glutamate, but only weakly by 10(-3)M N-acetyl-aspartylglutamate. The Ca2+ permeability (PCa/PCs) of the N-methyl-D-aspartate and non-N-methyl-D-aspartate receptors was 9.57 and 0.16, respectively. These results suggest that dorsal lateral geniculate nucleus relay neurons of the rat possessed both Ca2+-permeable N-methyl-D-aspartate receptors and less permeable non-N-methyl-D-aspartate (presumably AMPA) receptors, and that N-acetyl-aspartyl-glutamate mainly acts at N-methyl-D-aspartate receptors with a weak kainate-like action on non-N-methyl-D-aspartate receptors.
A selection problem arises whenever two or more competing systems seek simultaneous access to a restricted resource. Consideration of several selection architectures suggests there are significant advantages for systems which incorporate a central switching mechanism. We propose that the vertebrate basal ganglia have evolved as a centralized selection device, specialized to resolve conflicts over access to limited motor and cognitive resources. Analysis of basal ganglia functional architecture and its position within a wider anatomical framework suggests it can satisfy many of the requirements expected of an efficient selection mechanism.
The aim of this study was to illuminate behavioral and event-related potential (ERP) effects of attentional orienting and reorienting obtained in a newly developed auditory distraction paradigm, to provide more precise indicators about the neural generators of the ERP effects using scalp current density (SCD) analysis, and to evaluate the stability of the distraction effects.
In two sessions separated by 25 days, 10 subjects were presented with tones being of short (200 ms) and long (400 ms) duration equiprobably; tones were of high-probability standard or of low-probability deviant frequency. In Distraction condition, subjects had to behaviorally discriminate short from long tones. In Ignore condition, subjects were reading a book. Behavioral performance and multi-channel EEG were recorded.
Task-irrelevant frequency deviations prolonged reaction times in the duration discrimination task by more than 35 ms and elicited the MMN and P3a components of the event-related potential. The P3a was followed by a negative deflection called RON (reorienting negativity). P3a and RON were absent in Ignore condition. All effects were found to be highly stable between sessions (product-moment correlations between 0.76 and 0.90). SCD analysis suggested frontal generators for P3a and for RON.
It is demonstrated that small frequency deviations may yield distinct distraction effects in a tone duration discrimination task on a behavioral and on an electrophysiological level. Results support the hypothesis that frontal areas are involved in the exogenous orienting of attention (P3a) and in the reorienting of attention (RON). Due to the high stability of the deviance-related behavioral and ERP effects, this distraction paradigm may be utilized for clinical research.