Enhancing biomechanical machine learning with limited data: generating realistic synthetic posture data using generative artificial intelligence.

Objective: Biomechanical Machine Learning (ML) models, particularly deep-learning models, demonstrate the best performance when trained using extensive datasets. However, biomechanical data are frequently limited due to diverse challenges. Effective methods for augmenting data in developing ML models, specifically in the human posture domain, are scarce. Therefore, this study explored the feasibility of leveraging generative artificial intelligence (AI) to produce realistic synthetic posture data by utilizing three-dimensional posture data. Methods: Data were collected from 338 subjects through surface topography. A Variational Autoencoder (VAE) architecture was employed to generate and evaluate synthetic posture data, examining its distinguishability from real data by domain experts, ML classifiers, and Statistical Parametric Mapping (SPM). The benefits of incorporating augmented posture data into the learning process were exemplified by a deep autoencoder (AE) for automated feature representation. Results: Our findings highlight the challenge of differentiating synthetic data from real data for both experts and ML classifiers, underscoring the quality of synthetic data. This observation was also confirmed by SPM. By integrating synthetic data into AE training, the reconstruction error can be reduced compared to using only real data samples. Moreover, this study demonstrates the potential for reduced latent dimensions, while maintaining a reconstruction accuracy comparable to AEs trained exclusively on real data samples. Conclusion: This study emphasizes the prospects of harnessing generative AI to enhance ML tasks in the biomechanics domain.

Infection burden and its association with neurite orientation dispersion and density imaging markers in the UK Biobank.

BACKGROUND: Infection burden (IB), although linked to neurodegeneration, including Alzheimer's Disease (AD), has not been examined against neurite orientation, dispersion, and density imaging (NODDI) measures. METHODS: Among 38,803 UK Biobank adults (Age:40-70 years), we tested associations of total IB (IBtotal, 47.5 %) and hospital-treated IB (IBhosp, 9.7 %) with NODDI measures (5-15 years later), including volume fraction of Gaussian isotropic diffusion (ISOVF), intra-cellular volume fraction (ICVF) and orientation dispersion (OD) indices, using multiple linear regression models. RESULTS: Total and hospital-treated infection burdens (IBtotal and IBhosp) were associated with increased ISOVF, indicating increased free-water component. IBtotal was positively associated with OD, indicating that at higher IBtotal there was greater fanning of neurites. This was more evident in the lower cardiovascular health group. IBhosp was associated with higher OD, and lower ICVF at higher AD polygenic risk. Together, these findings indicate that both total and hospital-treated infections have effects on NODDI outcomes in the direction of poor brain health. These effects were largely homogeneous across cardiovascular health and AD polygenic risk groups, with some effects shown to be stronger at poor cardiovascular health and/or higher AD risk. CONCLUSIONS: Total and hospital-treated infections were associated with poorer white matter microstructure (higher ISOVF or OD or lower ICVF), with some heterogeneity across cardiovascular health and AD risk. Longitudinal studies with multiple repeats on neuroimaging markers in comparable samples are needed.

Influence of Lateral Sitting Wedges on the Rasterstereographically Measured Scoliosis Angle in Patients Aged 10-18 Years with Adolescent Idiopathic Scoliosis.

Adolescent idiopathic scoliosis (AIS) is a three-dimensional axial deviation of the spine diagnosed in adolescence. Despite a long daily sitting duration, there are no studies on whether scoliosis can be positively influenced by sitting on a seat wedge. For the prospective study, 99 patients with AIS were measured with the DIERS formetric III 4D average, in a standing position, on a level seat and with three differently inclined seat wedges (3°, 6° and 9°). The rasterstereographic parameters 'scoliosis angle' and 'lateral deviation RMS' were analysed. The side (ipsilateral/contralateral) on which the optimal correcting wedge was located in relation to the lumbar/thoraco-lumbar convexity was investigated. It was found that the greatest possible correction of scoliosis occurred with a clustering in wedges with an elevation on the ipsilateral side of the convexity. This clustering was significantly different from a uniform distribution (p < 0.001; chi-square = 35.697 (scoliosis angle); chi-square = 54.727 (lateral deviation RMS)). It should be taken into account that the effect of lateral seat wedges differs for individual types of scoliosis and degrees of severity. The possibility of having a positive effect on scoliosis while sitting holds great potential, which is worth investigating in follow-up studies.

Dynamic surface topography data for assessing intra- and interindividual variation of vertebral motion.

Spinal function is substantially related to the motion of the particular vertebrae and the spine as a whole. For systematic assessment of individual motion, data sets are required which cover the kinematics comprehensively. Additionally, the data should enable a comparison of inter- and intraindividual variation of vertebral orientation in dedicated motion tasks like gait. For this purpose, this article provides surface topography (ST) data which were acquired while the individual test persons were walking on a treadmill at three different speed levels (2 km/h, 3 km/h, 4 km/h). In each recording, ten full walking cycles were included per test case to enable a detailed analysis of motion patterns. The provided data reflects asymptomatic and pain-free volunteers. Each data set contains the vertebral orientation in all three motion directions for the vertebra prominens down to L4 as well as the pelvis. Additionally, spinal parameters like balance, slope, and lordosis / kyphosis parameters as well as an assignment of the motion data to single gait cycles are included. The complete raw data set without any preprocessing is provided. This allows to apply a broad range of further signal processing and evaluation steps in order to identify characteristic motion patterns as well as intra- and inter-individual variation of vertebral motion.

Creation and Evaluation of a Severity Classification of Hyperkyphosis and Hypolordosis for Exercise Therapy.

The rise in the occurrence of musculoskeletal disorders, such as thoracic hyperkyphosis (THK) or lumbar hypolordosis (LHL), is a result of demographic changes. Exercise therapy is an effective approach that can reduce related disabilities and costs. To ensure successful therapy, an individualized exercise program adapted to the severity of the disorder is expedient. Nevertheless, appropriate classification systems are scarce. This project aimed to develop and evaluate a severity classification focused on exercise therapy for patients with THK or LHL. A multilevel severity classification was developed and evaluated by means of an online survey. Reference limits of spinal shape angles were established by data from video rasterstereography of 201 healthy participants. A mean kyphosis angle of 50.03° and an average lordosis angle of 40.72° were calculated as healthy references. The strength of the multilevel classification consisting of the combination of subjective pain and objective spinal shape factors was confirmed by the survey (70% agreement). In particular, the included pain parameters were considered relevant by 78% of the experts. Even though the results of the survey provide important evidence for further analyses and optimization options of the classification system, the current version is still acceptable as therapeutic support.

Reference values and functional descriptions of transverse plane spinal dynamics during gait based on surface topography.

Spinal dynamics during gait have been of interest in research for many decades. Based on respective previous investigations, the pelvis is generally expected to be maximally forward rotated on the side of the reference leg at the beginning of each gait cycle and to reach its maximum counterrotation approximately at the end of the reference leg's stance phase. The pelvic-upper-thoracic-spine coordination converges towards an anti-phase movement pattern in high velocities during ambulation. The vertebral bodies around the seventh thoracic vertebra are considered to be an area of transition during human ambulation where no or at least little rotary motion can be observed. The respective cranial and caudal vertebrae meanwhile are expected to rotate conversely around this spinal point of intersection. However, these previous assumptions are based on scarce existing research, whereby only isolated vertebrae have been analyzed contemporaneously. Due to huge methodological differences in data capturing approaches, the results are additionally hardly comparable to each other and involved measurement procedures are often not implementable in clinical routines. Furthermore, none of the above-mentioned methods provided reference data for spinal motion during gait based on an appropriate number of healthy participants. Hence, the aim of this study was to present such reference data for spinal rotary motion of every vertebral body from C7 down to L4 and the pelvis derived from surface topographic back shape analyses in a cohort of 201 healthy participants walking on a treadmill at a given walking speed of 5 km/h. Additionally, the spine's functional movement behavior during gait should be described in the transverse plane based on data derived from this noninvasive, clinically suitable measurement approach and, in conclusion, the results shall be compared against those of previous research findings derived from other measurement techniques. Contrary to the previous functional understanding, the area of the mid-thoracic spine was found to demonstrate the largest amplitude of rotary motion of all investigated vertebrae and revealed an approximately counterrotated movement behavior compared to the rotary motion of the pelvis. In both directions, spinal rotation during gait seemed to be initiated by the pelvis. The overlying vertebrae followed in succession in the sense of an ongoing movement. Therefore, the point of intersection was not statically located in a specific anatomical section of the spine. Instead, it was found to be dynamic, ascending from one vertebra to the next from caudal to cranial in dependence of the pelvis's rotation initiation.

Consistency of vertebral motion and individual characteristics in gait sequences.

Vertebral motion reveals complex patterns, which are not yet understood in detail. This applies to vertebral kinematics in general but also to specific motion tasks like gait. For gait analysis, most of existing publications focus on averaging characteristics of recorded motion signals. Instead, this paper aims at analyzing intra- and inter-individual variation specifically and elaborating motion parameters, which are consistent during gait cycles of particular persons. For this purpose, a study design was utilized, which collected motion data from 11 asymptomatic test persons walking at different speed levels (2, 3, and 4 km/h). Acquisition of data was performed using surface topography. The motion signals were preprocessed in order to separate average vertebral orientations (neutral profiles) from basic gait cycles. Subsequently, a k-means clustering technique was applied to figure out, whether a discrimination of test persons was possible based on the preprocessed motion signals. The paper shows that each test sequence could be assigned to the particular test person without additional prior information. In particular, the neutral profiles appeared to be highly consistent intra-individually (across the gait cycles as well as speed levels), but substantially different between test persons. A full discrimination of test persons was achieved using the neutral profiles with respect to flexion/extension data. Based on this, these signals can be considered as individual characteristics for the particular test persons.

Reference Values for 3D Spinal Posture Based on Videorasterstereographic Analyses of Healthy Adults.

Visual examinations are commonly used to analyze spinal posture. Even though they are simple and fast, their interrater reliability is poor. Suitable alternatives should be objective, non-invasive, valid and reliable. Videorasterstereography (VRS) is a corresponding method that is increasingly becoming established. However, there is a lack of reference data based on adequate numbers of participants and structured subgroup analyses according to sex and age. We used VRS to capture the spinal posture of 201 healthy participants (aged 18-70 years) divided into three age cohorts. Three-dimensional reference data are presented for the global spine parameters and for every vertebral body individually (C7-L4) (here called the specific spine parameters). The vertebral column was found to be systematically asymmetric in the transverse and the coronal planes. Graphical presentations of the vertebral body posture revealed systematic differences between the subgroups; however, large standard deviations meant that these differences were not significant. In contrast, several global parameters (e.g., thoracic kyphosis and lumbar lordosis) indicated differences between the analyzed subgroups. The findings confirm the importance of presenting reference data not only according to sex but also according to age in order to map physiological posture changes over the life span. The question also arises as to whether therapeutic approximations to an almost symmetrical spine are biomechanically desirable.

Comprehensive visualization of spinal motion in gait sequences based on surface topography.

Analysis of spinal motion is considered to be important to assess function of the human spine. Surface topography (ST) is a method to record the vertebral orientation in 3D. Such measurements can be performed in static but also in dynamic situations like gait or other motion tasks. However, dynamic ST measurements are hard to interpret due to their complexity. The main goal of this paper is to provide comprehensive visualization tools which allow a more intuitive and comprehensive interpretation n of such measurements. In particular, juxtaposition and superimposition techniques are utilized to emphasize differences in motion characteristics. The method was applied to a test series of 12 healthy volunteers walking on a treadmill at various speed levels. It could be shown that the visualization tools are helpful to compare different motion sequences including an analysis of intra- and interindividual variation. Based on these techniques, it could be shown that the profiles of vertebral orientation remain considerable constant when one person was walking at different speed levels whereas they differed substantially between the different individuals. In contrast, the motion amplitudes contained high intra- and interindividual variation, i.e. between speed levels and different test persons. In summary, the paper demonstrates that appropriate visualization tools are helpful to interpret ST measurements and cope with the complexity of these data sets. In particular, they can be used to compare different motion sequences in a more comprehensive way.

Machine learning techniques demonstrating individual movement patterns of the vertebral column: the fingerprint of spinal motion.

Surface topography systems enable the capture of spinal dynamic movement; however, it is unclear whether vertebral dynamics are unique enough to identify individuals. Therefore, in this study, we investigated whether the identification of individuals is possible based on dynamic spinal data. Three different data representations were compared (automated extracted features using contrastive loss and triplet loss functions, as well as simple descriptive statistics). High accuracies indicated the possible existence of a personal spinal 'fingerprint', therefore enabling subject recognition. The present work forms the basis for an objective comparison of subjects and the transfer of the method to clinical use cases.

Evaluation of 3D vertebral and pelvic position by surface topography in asymptomatic females: presentation of normative reference data.

BACKGROUND: Deviations from a conventional physiologic posture are often a cause of complaint. According to current literature, the upright physiological spine posture exhibits inclinations in the sagittal plane but not in the coronal and transverse planes, but individual vertebral body positions of asymptomatic adults have rarely been described using surface topography. Therefore, this work aims to form a normative reference dataset for the thoracic and lumbar vertebral bodies and for the pelvis in all three planes in asymptomatic women. METHODS: In a prospective, cross-sectional, monocentric study, 100 pain-free asymptomatic women, aged 20-64 years were enrolled. Habitual standing positions of the trunk were measured using surface topography. Data were analyzed in all three planes. Age sub-analysis was: 1) ages ≤ 40 years and 2) ages ≥ 41 years. Two-sample t-tests were used for age comparisons of the vertebral bodies, vertebra prominence (VP)-L4, and global parameters. One-sample t-tests were used to test deviations from symmetrical zero positions of VP-L4. RESULTS: Coronal plane: on average, the vertebral bodies were tilted to the right between the VP and T4 (maximum: T2 - 1.8° ± 3.2), while between T6 and T11 they were tilted to the left (maximum: T7 1.1° ± 1.9). T5 and L2 were in a neutral position, overall depicting a mean right-sided lateral flexion from T2 to T7 (apex at T5). Sagittal plane: the kyphotic apex resided at T8 with - 0.5° ± 3.6 and the lumbar lordotic apex at L3 with - 2.1° ± 7.4. Transverse plane: participants had a mean vertebral body rotation to the right ranging from T6 to L4 (maximum: T11 - 2.2° ± 3.5). Age-specific differences were seen in the sagittal plane and had little effect on overall posture. CONCLUSIONS: Asymptomatic female volunteers standing in a habitual posture displayed an average vertebral rotation and lateral flexion to the right in vertebral segments T2-T7. The physiological asymmetrical posture of women could be considered in spinal therapies. With regard to spinal surgery, it should be clarified whether an approximation to an absolutely symmetrical posture is desirable from a biomechanical point of view? This data set can also be used as a reference in clinical practice. TRIAL REGISTRATION: This study was registered with WHO (INT: DRKS00010834) and approved by the responsible ethics committee at the Rhineland-Palatinate Medical Association (837.194.16).

Classification and Automated Interpretation of Spinal Posture Data Using a Pathology-Independent Classifier and Explainable Artificial Intelligence (XAI).

Clinical classification models are mostly pathology-dependent and, thus, are only able to detect pathologies they have been trained for. Research is needed regarding pathology-independent classifiers and their interpretation. Hence, our aim is to develop a pathology-independent classifier that provides prediction probabilities and explanations of the classification decisions. Spinal posture data of healthy subjects and various pathologies (back pain, spinal fusion, osteoarthritis), as well as synthetic data, were used for modeling. A one-class support vector machine was used as a pathology-independent classifier. The outputs were transformed into a probability distribution according to Platt's method. Interpretation was performed using the explainable artificial intelligence tool Local Interpretable Model-Agnostic Explanations. The results were compared with those obtained by commonly used binary classification approaches. The best classification results were obtained for subjects with a spinal fusion. Subjects with back pain were especially challenging to distinguish from the healthy reference group. The proposed method proved useful for the interpretation of the predictions. No clear inferiority of the proposed approach compared to commonly used binary classifiers was demonstrated. The application of dynamic spinal data seems important for future works. The proposed approach could be useful to provide an objective orientation and to individually adapt and monitor therapy measures pre- and post-operatively.

General method for automated feature extraction and selection and its application for gender classification and biomechanical knowledge discovery of sex differences in spinal posture during stance and gait.

Modern technologies enable to capture multiple biomechanical parameters often resulting in relational data. The current work proposes a generally applicable method comprising automated feature extraction, ensemble feature selection and classification to best capture the potentials of the data also for generating new biomechanical knowledge. Its benefits are demonstrated in the concrete biomechanically and medically relevant use case of gender classification based on spinal data for stance and gait. Very good results for accuracy were obtained using gait data. Dynamic movements of the lumbar spine in sagittal and frontal plane and of the pelvis in frontal plane best map gender differences.

Evaluation of a questionnaire-based diabetes screening concept in German patients with Stage III or IV periodontitis: A practice-based study.

BACKGROUND: This practice-based retrospective study evaluated a screening method for diabetes mellitus (DM) in patients with Stage III or IV periodontitis using the FINDRISC questionnaire. METHODS: Patients with Stage III or IV periodontitis who received FINDRISC screening in a German private dental practice were recruited. Individuals with positive FINDRISC scores (≥12, FINDRISC+) were referred for diabetological examination. Several general and periodontal findings from the patients' documentation were recorded and analyzed. RESULTS: A total of 179 patients (52.65 ± 11.49 years) were included. In DM screening, 24.6% (n = 44) patients were FINDRISC+, including all patients with currently known DM (21 of 21). Of the remaining FINDRISC+ patients, 82.6% (19 of 23) visited their general practitioner, and 63.2% (12 of 19, 7.6% of total cohort) had an HbA1c ≥5.7%. Accordingly, 75% of the FINDRISC+ patients were diabetologically conspicuous (HbA1c ≥ 5.7%), including those with already known DM. Patients with previously unknown DM showed higher mean age, more missing teeth, a higher periodontitis stage (more Stage IV) and more frequently teeth with suppuration compared with the diabetologically inconspicuous individuals (P <0.01). CONCLUSION: The FINDRISC questionnaire is appropriate for patients with Stage III or IV periodontitis and can be recommended in dental practice setting.

Effect of MRI-based semiautomatic size-assessment in cerebral metastases on the RANO-BM classification.

AIM: Evaluation of a semiautomatic software algorithm for magnetic resonance imaging (MRI)-based assessment of cerebral metastases in cancer patients. MATERIAL AND METHODS: Brain metastases (n = 131) in 38 patients, assessed by contrast-enhanced MRI, were retrospectively evaluated at two timepoints (baseline, follow-up) by two experienced neuroradiologists in a blinded manner. The response assessment in neuro-oncology (RANO) criteria for brain metastases (RANO-BM) were applied by means of a software (autoRANO-BM) as well as manually (manRANO-BM) at an interval of 3 weeks. RESULTS: The average diameter of metastases was 12.03 mm (SD ± 6.66 mm) for manRANO-BM and 13.97 mm (SD ± 7.76 mm) for autoRANO-BM. Diameter figures were higher when using semiautomatic measurements (median = 11.8 mm) as compared to the manual ones (median = 10.2 mm; p = 0.000). Correlation coefficients for intra-observer variability were 0.993 (autoRANO-BM) and 0.979 (manRANO-BM). The interobserver variability (R1/R2) was 0.936/0.965 for manRANO-BM and 0.989/0.998 for autoRANO-BM. A total of 19 lesions (15%) were classified differently when using semiautomatic measurements. In 14 cases with suspected disease progression by manRANO-BM a stable course was found according to autoRANO-BM. CONCLUSION: Computerized measuring techniques can aid in the assessment of cerebral metastases by reducing examiner-dependent effects and may consequently result in a different classification according to RANO-BM criteria.

Multifocal motor neuropathy in Austria: a nationwide survey of clinical features and response to treatment.

BACKGROUND AND OBJECTIVES: Multifocal motor neuropathy (MMN) is a rare neuropathy and detailed descriptions of larger patient cohorts are scarce. The objective of this study was to evaluate epidemiological, clinical, and laboratory features of MMN patients and their response to treatment in Austria and to compare these data with those from the literature. METHODS: Anonymized demographic and clinical data about MMN patients until 31.12.2017 were collected from registered Austrian neurologists. Exploratory statistics on clinical and laboratory features as well as treatment regimens and responses were performed. RESULTS: 57 Patients with MMN were identified, resulting in a prevalence of 0.65/100.000. Mean age of onset was 44.1 ± 13.1 years, the diagnostic delay 5.5 ± 8.4 years. In 77% of patients, symptom onset was in the upper limbs, and in 92%, it occurred in distal muscles. Proximal onset was never observed in the lower limbs. At the final follow-up, the majority of patients had atrophy (88%) in affected regions. Definite motor conduction blocks (CB) were found in 54 patients. Anti-GM1-IgM antibodies were present in 43%. Treatment with intravenous immunoglobulins improved muscle strength and INCAT score initially, but at last follow-up, both scores deteriorated to values before treatment. DISCUSSION: The findings of the present study corroborate the previous findings in MMN. Onset typically occurs in the upper limbs and mostly distal, CBs are found in the majority of cases, while anti-GM1-IgM antibodies are detected in only approximately 40%. Our study underlines that the initial good response to treatment fades over time.

Alloantigen expression on malignant cells and healthy host tissue influences graft-versus-tumor reactions after allogeneic hematopoietic stem cell transplantation.

Durable remissions of hematological malignancies regularly observed following allogeneic hematopoietic stem cell transplantation (aHSCT) are due to the conditioning regimen, as well as an immunological phenomenon called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT) effect. The development of GVL is closely linked to graft-versus-host disease (GVHD), the main side effect associated with aHSCT. Both, GVHD and GVL are mediated by donor T cells that are initially activated by antigen-presenting cells that present recipient-derived alloantigens in the context of either matched or mismatched MHC class I molecules. Using murine models of aHSCT we show that ubiquitously expressed minor histocompatibility alloantigens (mHAg) are no relevant target for GVT effects. Interestingly, certain ubiquitously expressed MHC alloantigens augmented GVT effects early after transplantation, while others did not. The magnitude of GVT effects correlated with tumor infiltration by CD8+ cytotoxic T cells and tumor cell apoptosis. Furthermore, the immune response underlying GVHD and GVT was oligoclonal, highlighting that immunodominance is an important factor during alloimmune responses. These results emphasize that alloantigen expression on non-hematopoietic tissues can influence GVT effects in a previously unrecognized fashion. These findings bear significance for harnessing optimal GVL effects in patients receiving aHSCT.

Cross-Sectional and Longitudinal Effects of CREB1 Genotypes on Individual Differences in Memory and Executive Function: Findings from the BLSA.

Purpose: Previously, we have shown that the SNP rs10932201 genotype of the cyclic AMP responsive element binding protein 1 gene (CREB1) contributes to individual differences in executive and memory function at the neural system and behavioral levels in healthy, young adults. However, longitudinal effects of CREB1 genotypes on cognition have not yet been addressed. Furthermore we were interested in replicating associations between CREB1 genotypes and human cognition in previous cross-sectional studies and explore whether APOE𝜀4 status might modify these relations. Materials and Methods: We investigated whether common, independent tag SNPs within CREB1 (rs2253206, rs10932201, rs6785) influence individual differences in age-related longitudinal change and level of executive function and memory performance independent of baseline age, sex, APOE𝜀4 status, and education. Our analysis included data from cognitively unimpaired older adults participating in the Baltimore Longitudinal Study of Aging. Eleven measures from six cognitive tests (sample sizes range 617-786) were analyzed using linear mixed effects and generalized estimating equations models. Mean baseline age ranged from 50 to 69 years and mean time of follow-up (interval) ranged from 8 to 22 years. Results: We found significant effects of all three CREB1 SNPs on performance level and/or longitudinal change in performance based on eight measures assessing semantic memory, episodic memory, or both executive function and semantic memory. SNP rs10932201 showed the most significant and largest effect (Cohen's d = -0.70, p < 0.01) on age-related longitudinal decline of semantic memory. Additionally, we show interactions between all three CREB1 SNPs and APOE𝜀4 status on age-related longitudinal declines and levels of memory and executive function. Conclusion: Our results suggest that CREB1 genotypes independently and by interactions with APOE𝜀4 status contribute to individual differences in cognitive aging.

Investigating the Impact of a Genome-Wide Supported Bipolar Risk Variant of MAD1L1 on the Human Reward System.

Recent genome-wide association studies have identified MAD1L1 (mitotic arrest deficient-like 1) as a susceptibility gene for bipolar disorder and schizophrenia. The minor allele of the single-nucleotide polymorphism (SNP) rs11764590 in MAD1L1 was associated with bipolar disorder. Both diseases, bipolar disorder and schizophrenia, are linked to functional alterations in the reward system. We aimed at investigating possible effects of the MAD1L1 rs11764590 risk allele on reward systems functioning in healthy adults. A large homogenous sample of 224 young (aged 18-31 years) participants was genotyped and underwent functional magnetic resonance imaging (fMRI). All participants performed the 'Desire-Reason Dilemma' paradigm investigating the neural correlates that underlie reward processing and active reward dismissal in favor of a long-term goal. We found significant hypoactivations of the ventral tegmental area (VTA), the bilateral striatum and bilateral frontal and parietal cortices in response to conditioned reward stimuli in the risk allele carriers compared with major allele carriers. In the dilemma situation, functional connectivity between prefrontal brain regions and the ventral striatum was significantly diminished in the risk allele carriers. Healthy risk allele carriers showed a significant deficit of their bottom-up response to conditioned reward stimuli in the bilateral VTA and striatum. Furthermore, functional connectivity between the ventral striatum and prefrontal areas exerting top-down control on the mesolimbic reward system was reduced in this group. Similar alterations in reward processing and disturbances of prefrontal control mechanisms on mesolimbic brain circuits have also been reported in bipolar disorder and schizophrenia. Together, these findings suggest the existence of an intermediate phenotype associated with MAD1L1.

CREB1 Genotype Modulates Adaptive Reward-Based Decisions in Humans.

Cyclic AMP response element-binding protein (CREB) contributes to adaptation of mesocorticolimbic networks by modulating activity-regulated transcription and plasticity in neurons. Activity or expression changes of CREB in the nucleus accumbens (NAc) and orbital frontal cortex (OFC) interact with behavioral changes during reward-motivated learning. However, these findings from animal models have not been evaluated in humans. We tested whether CREB1 genotypes affect reward-motivated decisions and related brain activation, using BOLD fMRI in 224 young and healthy participants. More specifically, participants needed to adapt their decision to either pursue or resist immediate rewards to optimize the reward outcome. We found significant CREB1 genotype effects on choices to pursue increases of the reward outcome and on BOLD signal in the NAc, OFC, insula cortex, cingulate gyrus, hippocampus, amygdala, and precuneus during these decisions in comparison with those decisions avoiding total reward loss. Our results suggest that CREB1 genotype effects in these regions could contribute to individual differences in reward- and associative memory-based decision-making.