Bridging flexible goal-directed cognition and consciousness: The Goal-Aligning Representation Internal Manipulation theory.

Goal-directed manipulation of internal representations is a key element of human flexible behaviour, while consciousness is commonly associated with higher-order cognition and human flexibility. Current perspectives have only partially linked these processes, thus preventing a clear understanding of how they jointly generate flexible cognition and behaviour. Moreover, these limitations prevent an effective exploitation of this knowledge for technological scopes. We propose a new theoretical perspective that extends our 'three-component theory of flexible cognition' toward higher-order cognition and consciousness, based on the systematic integration of key concepts from Cognitive Neuroscience and AI/Robotics. The theory proposes that the function of conscious processes is to support the alignment of representations with multi-level goals. This higher alignment leads to more flexible and effective behaviours. We analyse here our previous model of goal-directed flexible cognition (validated with more than 20 human populations) as a starting GARIM-inspired model. By bridging the main theories of consciousness and goal-directed behaviour, the theory has relevant implications for scientific and technological fields. In particular, it contributes to developing new experimental tasks and interpreting clinical evidence. Finally, it indicates directions for improving machine learning and robotics systems and for informing real-world applications (e.g., in digital-twin healthcare and roboethics).

Low Colorectal Cancer Risk After Resection of High-Risk Pedunculated Polyps.

BACKGROUND: Post-fecal immunochemical test (FIT) colonoscopy represents a setting with an enriched prevalence of advanced adenomas. Due to an expected higher risk of colorectal cancer (CRC), postpolypectomy surveillance is recommended, generating a substantially increased load on endoscopy services. The aim of our study was to investigate postpolypectomy CRC risk in a screening population of FIT+ subjects after resection of low-risk adenomas (LRAs) or high-risk adenomas (HRAs). METHODS: We retrieved data from a cohort of patients undergoing postpolypectomy surveillance within a FIT-based CRC screening program in Italy between 2002 and 2017 and followed-up to December 2021. Main outcomes were postpolypectomy CRC incidence and mortality risks according to type of adenoma (LRA/HRA) removed at colonoscopy as well as morphology, size, dysplasia, and location of the index lesion. We adopted as comparators FIT+/colonoscopy-negative and FIT- patients. The absolute risk was calculated as the number of incident CRCs per 100,000 person-years of follow-up. We used Cox multivariable regression models to identify associations between CRC risks and patient- and polyp-related variables. RESULTS: Overall, we included 87,248 post-FIT+ colonoscopies (133 endoscopists). Of these, 42,899 (49.2%) were negative, 21,650 (24.8%) had an LRA, and 22,709 (26.0%) an HRA. After a median follow-up of 7.25 years, a total of 635 CRCs were observed. For patients with LRAs, CRC incidence (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.92-1.53) was not increased compared with the FIT+/colonoscopy-negative group, while for HRAs a significant increase in CRC incidence (HR, 1.53; 95% CI, 1.14-2.04) was found. The presence of 1 or more risk factors among proximal location, nonpedunculated morphology, and high-grade dysplasia explained most of this excess CRC risk in the HRA group (HR, 1.85; 95% CI, 1.36-2.52). Patients with only distal pedunculated polyps without high-grade dysplasia, representing 39.2% of HRA, did not have increased risk compared with the FIT- group (HR, 0.87; 95% CI, 0.59-1.28). CONCLUSIONS: CRC incidence is significantly higher in patients with HRAs diagnosed at colonoscopy. However, such excess risk does not appear to apply to patients with only distal pedunculated polyps without high-grade dysplasia, an observation that could potentially reduce the burden of surveillance in FIT programs.

Adenoma Detection Rate and Colorectal Cancer Risk in Fecal Immunochemical Test Screening Programs : An Observational Cohort Study.

BACKGROUND: Colorectal cancer (CRC) screening programs based on fecal immunochemical tests (FITs) represent the standard of care for population-based interventions. Their benefit depends on the identification of neoplasia at colonoscopy after FIT positivity. Colonoscopy quality measured by adenoma detection rate (ADR) may affect screening program effectiveness. OBJECTIVE: To examine the association between ADR and postcolonoscopy CRC (PCCRC) risk in a FIT-based screening program. DESIGN: Retrospective population-based cohort study. SETTING: Fecal immunochemical test-based CRC screening program between 2003 and 2021 in northeastern Italy. PATIENTS: All patients with a positive FIT result who had a colonoscopy were included. MEASUREMENTS: The regional cancer registry supplied information on any PCCRC diagnosed between 6 months and 10 years after colonoscopy. Endoscopists' ADR was categorized into 5 groups (20% to 39.9%, 40% to 44.9%, 45% to 49.9%, 50% to 54.9%, and 55% to 70%). To examine the association of ADR with PCCRC incidence risk, Cox regression models were fitted to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Of the 110 109 initial colonoscopies, 49 626 colonoscopies done by 113 endoscopists between 2012 and 2017 were included. After 328 778 person-years follow-up, 277 cases of PCCRC were diagnosed. Mean ADR was 48.3% (range, 23% and 70%). Incidence rates of PCCRC from lowest to highest ADR group were 13.13, 10.61, 7.60, 6.01, and 5.78 per 10 000 person-years. There was a significant inverse association between ADR and PCCRC incidence risk, with a 2.35-fold risk increase (95% CI, 1.63 to 3.38) in the lowest group compared with the highest. The adjusted HR for PCCRC associated with 1% increase in ADR was 0.96 (CI, 0.95 to 0.98). LIMITATION: Adenoma detection rate is partly determined by FIT positivity cutoff; exact values may vary in different settings. CONCLUSION: In a FIT-based screening program, ADR is inversely associated with PCCRC incidence risk, mandating appropriate colonoscopy quality monitoring in this setting. Increasing endoscopists' ADR may significantly reduce PCCRC risk. PRIMARY FUNDING SOURCE: None.

A Natural Human-Drone Embodied Interface: Empirical Comparison With a Traditional Interface.

Despite the importance of usability in human-machine interaction (HMI), most commonly used devices are not usable by all potential users. In particular, users with low or null technological experience, or with special needs, require carefully designed systems and easy-to-use interfaces supporting recognition over recall. To this purpose, Natural User Interfaces (NUIs) represent an effective strategy as the user's learning is facilitated by features of the interface that mimic the human "natural" sensorimotor embodied interactions with the environment. This paper compares the usability of a new NUI (based on an eye-tracker and hand gesture recognition) with a traditional interface (keyboard) for the distal control of a simulated drone flying in a virtual environment. The whole interface relies on "dAIsy", a new software allowing the flexible use of different input devices and the control of different robotic platforms. The 59 users involved in the study were required to complete two tasks with each interface, while their performance was recorded: (a) exploration: detecting trees embedded in an urban environment; (b) accuracy: guiding the drone as accurately and fast as possible along a predefined track. Then they were administered questionnaires regarding the user's background, the perceived embodiment of the device, and the perceived quality of the virtual experience while either using the NUI or the traditional interface. The results appear controversial and call for further investigation: (a) contrary to our hypothesis, the specific NUI used led to lower performance than the traditional interface; (b) however, the NUI was evaluated as more natural and embodied. The final part of the paper discusses the possible causes underlying these results that suggest possible future improvements of the NUI.

A multi-expert ensemble system for predicting Alzheimer transition using clinical features.

Alzheimer's disease (AD) diagnosis often requires invasive examinations (e.g., liquor analyses), expensive tools (e.g., brain imaging) and highly specialized personnel. The diagnosis commonly is established when the disorder has already caused severe brain damage, and the clinical signs begin to be apparent. Instead, accessible and low-cost approaches for early identification of subjects at high risk for developing AD years before they show overt symptoms are fundamental to provide a critical time window for more effective clinical management, treatment, and care planning. This article proposes an ensemble-based machine learning algorithm for predicting AD development within 9 years from first overt signs and using just five clinical features that are easily detectable with neuropsychological tests. The validation of the system involved both healthy individuals and mild cognitive impairment (MCI) patients drawn from the ADNI open dataset, at variance with previous studies that considered only MCI. The system shows higher levels of balanced accuracy, negative predictive value, and specificity than other similar solutions. These results represent a further important step to build a preventive fast-screening machine-learning-based tool to be used as a part of routine healthcare screenings.

A neuro-inspired computational model of life-long learning and catastrophic interference, mimicking hippocampus novelty-based dopamine modulation and lateral inhibitory plasticity.

The human brain has a remarkable lifelong learning capability to acquire new experiences while retaining previously acquired information. Several hypotheses have been proposed to explain this capability, but the underlying mechanisms are still unclear. Here, we propose a neuro-inspired firing-rate computational model involving the hippocampus and surrounding areas, that encompasses two key mechanisms possibly underlying this capability. The first is based on signals encoded by the neuromodulator dopamine, which is released by novel stimuli and enhances plasticity only when needed. The second is based on a homeostatic plasticity mechanism that involves the lateral inhibitory connections of the pyramidal neurons of the hippocampus. These mechanisms tend to protect neurons that have already been heavily employed in encoding previous experiences. The model was tested with images from the MNIST machine learning dataset, and with more naturalistic images, for its ability to mitigate catastrophic interference in lifelong learning. The results show that the proposed biologically grounded mechanisms can effectively enhance the learning of new stimuli while protecting previously acquired knowledge. The proposed mechanisms could be investigated in future empirical animal experiments and inspire machine learning models.

A Biologically Inspired Neural Network Model to Gain Insight Into the Mechanisms of Post-Traumatic Stress Disorder and Eye Movement Desensitization and Reprocessing Therapy.

Eye movement desensitization and reprocessing (EMDR) therapy is a well-established therapeutic method to treat post-traumatic stress disorder (PTSD). However, how EMDR exerts its therapeutic action has been studied in many types of research but still needs to be completely understood. This is in part due to limited knowledge of the neurobiological mechanisms underlying EMDR, and in part to our incomplete understanding of PTSD. In order to model PTSD, we used a biologically inspired computational model based on firing rate units, encompassing the cortex, hippocampus, and amygdala. Through the modulation of its parameters, we fitted real data from patients treated with EMDR or classical exposure therapy. This allowed us to gain insights into PTSD mechanisms and to investigate how EMDR achieves trauma remission.

A computational model of inner speech supporting flexible goal-directed behaviour in Autism.

Experimental and computational studies propose that inner speech boosts categorisation skills and executive functions, making human behaviour more focused and flexible. In addition, many clinical studies highlight a relationship between poor inner-speech and an executive impairment in autism spectrum condition (ASC), but contrasting findings are reported. Here we directly investigate the latter issue through a previously implemented and validated computational model of the Wisconsin Cards Sorting Tests. In particular, the model was applied to explore potential individual differences in cognitive flexibility and inner speech contribution in autistic and neurotypical participants. Our model predicts that the use of inner-speech could increase along the life-span of neurotypical participants but would be reduced in autistic ones. Although we found more attentional failures (i.e., wrong behavioural rule switches) in autistic children/teenagers and more perseverative behaviours in autistic young/older adults, only autistic children and older adults exhibited a lower performance (i.e., fewer consecutive correct rule switches) than matched control groups. Overall, our results corroborate the idea that the reduced use of inner speech could represent a disadvantage for autistic children and autistic older adults. Moreover, the results suggest that cognitive-behavioural therapies should focus on developing inner speech skills in autistic children as this could provide cognitive support throughout their whole life span.

A non-invasive combined strategy to improve the appropriateness of upper gastrointestinal endoscopy.

Background and aim Increasing the appropriateness of upper gastrointestinal endoscopy (UGIE) improves the quality of care while containing costs. The aim of this study was to improve the appropriateness of UGIE through a process involving evaluation of prescriptions and the use of a non-invasive alternative. Materials and methods A senior endoscopist evaluated the appropriateness of all outpatient referrals for UGIE and established the proper timing. Referrals were either accepted and programmed, canceled, or substituted by a non-invasive evaluation of gastric function, determining serum levels of gastrin-17 (G17), Pepsinogen I (PGI) and II (PGII), and antibodies against Helicobacter pylori. Results A total of 5102 requests for UGIE examinations were evaluated; 540 (10.4%) were inappropriate and had been prescribed for: gastroesophageal reflux disease (n=307), surveillance with erroneous timing (n=113), dyspepsia (n=66), other indications (n=20), and absence of written indication (n=34). Gastric function was evaluated in 282/540 patients; findings included normal values in 94 patients without proton-pump inhibitor therapy (PPI) and in 48 on PPI, active H pylori infection in 56, previous H pylori infection in 30, GERD in n=50, and atrophic gastritis in n=4. UGIE was performed in the latter 4 cases.  Within 2 years (range 1-22 months) of the initial refusal, 105/504 patients underwent UGIE, with normal endoscopic findings in 71/105 (67.5%), and with no cases of cancer. Conclusions This strategy, based on a strict control of prescriptions, is effective to increase the appropriateness while containing public health costs. The use of gastric function testing improves patient selection for UGIE endoscopy.

Emotions Modulate Affordances-Related Motor Responses: A Priming Experiment.

Traditionally, research on affordances and emotions follows two separate routes. For the first time, this article explicitly links the two phenomena by investigating whether, in a discrimination task (artifact vs. natural object), the motivational states induced by emotional images can modulate affordances-related motor response elicited by dangerous and neutral graspable objects. The results show faster RTs: (i) for both neutral and dangerous objects with neutral images; (ii) for dangerous objects with pleasant images; (iii) for neutral objects with unpleasant images. Overall, these data support a significant effect of emotions on affordances. The article also proposes a brain neural network underlying emotions and affordance interplay.

Integrating unsupervised and reinforcement learning in human categorical perception: A computational model.

Categorical perception identifies a tuning of human perceptual systems that can occur during the execution of a categorisation task. Despite the fact that experimental studies and computational models suggest that this tuning is influenced by task-independent effects (e.g., based on Hebbian and unsupervised learning, UL) and task-dependent effects (e.g., based on reward signals and reinforcement learning, RL), no model studies the UL/RL interaction during the emergence of categorical perception. Here we have investigated the effects of this interaction, proposing a system-level neuro-inspired computational architecture in which a perceptual component integrates UL and RL processes. The model has been tested with a categorisation task and the results show that a balanced mix of unsupervised and reinforcement learning leads to the emergence of a suitable categorical perception and the best performance in the task. Indeed, an excessive unsupervised learning contribution tends to not identify task-relevant features while an excessive reinforcement learning contribution tends to initially learn slowly and then to reach sub-optimal performance. These results are consistent with the experimental evidence regarding categorical activations of extrastriate cortices in healthy conditions. Finally, the results produced by the two extreme cases of our model can explain the existence of several factors that may lead to sensory alterations in autistic people.

Neural Circuits Underlying Social Fear in Rodents: An Integrative Computational Model.

Social avoidance in rodents arises from a complex interplay between the prefrontal cortex and subcortical structures, such as the ventromedial hypothalamus and the dorsal periaqueductal gray matter. Experimental studies are revealing the contribution of these areas, but an integrative view and model of how they interact to produce adaptive behavior are still lacking. Here, we present a computational model of social avoidance, proposing a set of integrated hypotheses on the possible macro organization of the brain system underlying this phenomenon. The model is validated by accounting for several different empirical findings and produces predictions to be tested in future experiments.

Barrett's esophagus: results from an Italian cohort with tight endoscopic surveillance.

BACKGROUND AND AIM: Barrett's Esophagus represents a condition that predisposes to the development of esophageal adenocarcinoma. The aim of the present study was to analyze the demographic and clinical characteristics of patients with BE, to establish the presence of risk factors for this condition, and to determine the frequency of dysplastic lesions as well as the evolution towards adenocarcinoma under tight endoscopic control. METHODS: In this study, we retrospectively collected and analyzed data from a cohort of patients with Barrett's Esophagus identified through endoscopic records of ULSS7 in Northern Italy, who underwent upper esophagogastroduodenoscopy over a 10-year period from July 2008 to December 2020. RESULTS: A total of 264 patients were identified as having BE and included in the study. Mean follow-up was 6.7 years (range: 3 months-13 years). Demographic characteristics of the study population included mean age of 62.7 years (range 33-90 years), with 62.5% of the study population being aged 60 or older, and a male predominance. Females were significantly older than males (65.7 years, range 37-90 vs 61.9 years, range 33-87, p=0.043, respectively). CONCLUSIONS: The present study confirms the importance of tight endoscopic control in the management of BE, favoring early detection of BE degeneration towards high-grade dysplasia or adenocarcinoma. In a subset of patients with high-risk factors including male sex, cigarette smoking and heavy alcohol intake, it may be worthwhile to consider endoscopic control over time in order to detect the development of BE.

Internal manipulation of perceptual representations in human flexible cognition: A computational model.

Executive functions represent a set of processes in goal-directed cognition that depend on integrated cortical-basal ganglia brain systems and form the basis of flexible human behaviour. Several computational models have been proposed for studying cognitive flexibility as a key executive function and the Wisconsin card sorting test (WCST) that represents an important neuropsychological tool to investigate it. These models clarify important aspects that underlie cognitive flexibility, particularly decision-making, motor response, and feedback-dependent learning processes. However, several studies suggest that the categorisation processes involved in the solution of the WCST include an additional computational stage of category representation that supports the other processes. Surprisingly, all models of the WCST ignore this fundamental stage and they assume that decision making directly triggers actions. Thus, we propose a novel hypothesis where the key mechanisms of cognitive flexibility and goal-directed behaviour rely on the acquisition of suitable representations of percepts and their top-down internal manipulation. Moreover, we propose a neuro-inspired computational model to operationalise this hypothesis. The capacity of the model to support cognitive flexibility was validated by systematically reproducing and interpreting the behaviour exhibited in the WCST by young and old healthy adults, and by frontal and Parkinson patients. The results corroborate and further articulate the hypothesis that the internal manipulation of representations is a core process in goal-directed flexible cognition.

Low Levels of Gastrin 17 are Related with Endoscopic Findings of Esophagitis and Typical Symptoms of GERD.

BACKGROUND AND AIMS: In clinical practice, most patients with symptoms suggestive of gastroesophageal reflux disease (GERD) undergo esophago-gastro-duodenoscopy (EGD), despite its low sensitivity in detecting reflux stigmata. Gastrin 17 (G-17) has been proposed to be related with GERD, due to the negative feedback between acid secretion and this hormone. We assessed the clinical usefulness of fasting G-17 serum determination for a non-invasive diagnosis of GERD in patients with typical symptoms. METHODS: We consecutively enrolled patients complaining of typical GERD symptoms in two different settings: a single referral center and a primary care setting. Control groups consisted of dyspeptic patients. All subjects underwent assessment of serum levels of G-17 and EGD. RESULTS: At the academic hospital, 100 GERD patients (n=89 with erosive esophagitis and 11 with Barrett's esophagus) had statistically significant low levels of G-17 as compared with 184 dyspeptic patients (1.7±1.2 pg/L vs 8.9±5.7 pg/L p<0.0001). Similarly, in the primary care setting, 163 GERD patients had statistically significant low levels of G-17 as compared with 132 dyspeptic patients (0.5±0.2 pg/L vs. 4.0±2.6 pg/L, p<0.0001). Moreover, in the primary care setting, no statistically significant differences were found for G-17 levels between patients with erosive and non-erosive reflux pattern (0.4±0.2 vs 0.7±0.3; p=0.08). In primary care, the accuracy of G-17 less than 1 pg/L to diagnose non-invasively GERD was 94.3%. CONCLUSIONS: Low levels of G-17 were detected in patients with erosive esophagitis and Barrett's esophagus in a referral center and in patients with typical GERD symptoms in a sample of patients from a primary care setting.

A computational model of language functions in flexible goal-directed behaviour.

The function of language in high-order goal-directed human cognition is an important topic at the centre of current debates. Experimental evidence shows that inner speech, representing a self-directed form of language, empowers cognitive processes such as working memory, perception, categorization, and executive functions. Here we study the relations between inner speech and processes like feedback processing and cognitive flexibility. To this aim we propose a computational model that controls an artificial agent who uses inner speech to internally manipulate its representations. The agent is able to reproduce human behavioural data collected during the solution of the Wisconsin Card Sorting test, a neuropsychological test measuring cognitive flexibility, both in the basic condition and when a verbal shadowing protocol is used. The components of the model were systematically lesioned to clarify the specific impact of inner speech on the agent's behaviour. The results indicate that inner speech improves the efficiency of internal representation manipulation. Specifically, it makes the representations linked to specific visual features more disentangled, thus improving the agent's capacity to engage/disengage attention on stimulus features after positive/negative action outcomes. Overall, the model shows how inner speech could improve goal-directed internal manipulation of representations and enhance behavioural flexibility.

A generative spiking neural-network model of goal-directed behaviour and one-step planning.

In mammals, goal-directed and planning processes support flexible behaviour used to face new situations that cannot be tackled through more efficient but rigid habitual behaviours. Within the Bayesian modelling approach of brain and behaviour, models have been proposed to perform planning as probabilistic inference but this approach encounters a crucial problem: explaining how such inference might be implemented in brain spiking networks. Recently, the literature has proposed some models that face this problem through recurrent spiking neural networks able to internally simulate state trajectories, the core function at the basis of planning. However, the proposed models have relevant limitations that make them biologically implausible, namely their world model is trained 'off-line' before solving the target tasks, and they are trained with supervised learning procedures that are biologically and ecologically not plausible. Here we propose two novel hypotheses on how brain might overcome these problems, and operationalise them in a novel architecture pivoting on a spiking recurrent neural network. The first hypothesis allows the architecture to learn the world model in parallel with its use for planning: to this purpose, a new arbitration mechanism decides when to explore, for learning the world model, or when to exploit it, for planning, based on the entropy of the world model itself. The second hypothesis allows the architecture to use an unsupervised learning process to learn the world model by observing the effects of actions. The architecture is validated by reproducing and accounting for the learning profiles and reaction times of human participants learning to solve a visuomotor learning task that is new for them. Overall, the architecture represents the first instance of a model bridging probabilistic planning and spiking-processes that has a degree of autonomy analogous to the one of real organisms.

A Computational Model Integrating Multiple Phenomena on Cued Fear Conditioning, Extinction, and Reinstatement.

Conditioning, extinction, and reinstatement are fundamental learning processes of animal adaptation, also strongly involved in human pathologies such as post-traumatic stress disorder, anxiety, depression, and dependencies. Cued fear conditioning, extinction, restatement, and systematic manipulations of the underlying brain amygdala and medial prefrontal cortex, represent key experimental paradigms to study such processes. Numerous empirical studies have revealed several aspects and the neural systems and plasticity underlying them, but at the moment we lack a comprehensive view. Here we propose a computational model based on firing rate leaky units that contributes to such integration by accounting for 25 different experiments on fear conditioning, extinction, and restatement, on the basis of a single neural architecture having a structure and plasticity grounded in known brain biology. This allows the model to furnish three novel contributions to understand these open issues: (a) the functioning of the central and lateral amygdala system supporting conditioning; (b) the role played by the endocannabinoids system in within- and between-session extinction; (c) the formation of three important types of neurons underlying fear processing, namely fear, extinction, and persistent neurons. The model integration of the results on fear conditioning goes substantially beyond what was done in previous models.

Functional Dyspesia.

Dyspepsia is a functional GI disorder consisting in a wide range of symptoms. The main diagnostic challenge has been whether to perform an EGD or an abdominal US in order not to miss organic lesions, but to avoid unnecessary and sometimes invasive tests. Pepsinogen serology has been proposed as an useful non-invasive test to explore the status of the gastric mucosa, suggesting this strategy as an adequate approach in management of dyspepsia. In a primary care setting, 266 dyspeptic patients were investigated to establish the proper diagnosis. The workup included upper GI endoscopy with biopsies, a structured questionnaire including type and severity of symptoms, serological determination of serum pepsinogens, gastrin 17 and IgG against Hp. Inclusion criteria were dyspeptic symptoms (epigastric pain, nausea and/or vomiting, post prandial fullness, early satiation) lasting more than 1 year and the association between symptoms and food ingestion.. Helicobacter pylori infection was present in 114 subjects, characterized by high levels of pepsinogen II and IgG against Hp. Twenty subjects were classified according with the diagnosis of chronic body atrophic gastritis. Nausea and post prandial fullness were the most frequent symptoms (48% and 41%, respectively) in the studied population, followed by epigastric pain and early satiation (37% and 26% respectively). A diagnosis of normality by serological diagnosis was found in half of patients experiencing epigastric pain and in about 60% of subjects with the three other symptoms (nausea, post prandial fullness, and early satiation). In conclusion, this experience confirms the clinical usefulness of serology in dyspepsia, contributing to correctly diagnosing CAG and H.p. infection in such patients and providing a good correlation with the clinical picture.

Computational Modeling of Catecholamines Dysfunction in Alzheimer's Disease at Pre-Plaque Stage.

BACKGROUND: Alzheimer's disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. OBJECTIVE: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). METHODS: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. RESULTS: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. CONCLUSION: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.