Apathy

Apathy is a neurocognitive syndrome characterized by reduced goal-directed behaviors, contributing to decreased patient and caregiver quality of life. Apathy pathophysiology involves disruption of cortico-striato-thalamo-cortical loops, modulated by several neurotransmitter systems including dopamine and acetylcholine, thus complexifying pharmacological management. Post-stroke apathy (PSA) can provide a proper in vivo model to study the underlying neurochemical substrates of apathy as a syndrome. The present project aims to provide a better characterization of the cholinergic and dopaminergic functioning in apathy as a syndrome. In order to precise the respective alterations of these two systems, investigators will use a positron emission tomography (PET) molecular imaging of dopaminergic (with \[18F\]-FDOPA, a marker of the decarboxylating enzyme of dopamine) and - for the first time in apathetic patients - cholinergic (with \[18F\]-FEOBV, a marker of the vesicular acetylcholine transporter) transmissions in 15 apathetic and 15 unapathetic patients 3 months after stroke, without overlapping depression. This dual imaging study may provide help in guiding therapeutic management of PSA. The functional network analysis allowed by functional MRI is crucial to complement regional neurotransmitter deficits observed with PET. Altogether, a multimodal approach in apathy, combining PET and MRI, can allow identifying which circuits of the cortico-striato-thalamo-cortical loops are disrupted and how these circuits are modulated by other neurotransmitters.

SENS'REM is a pilot feasibility study evaluating a new non-drug therapeutic program based on multisensory reminiscence using immersive virtual reality in older adults living in nursing homes or long-term care units who present cognitive impairment and apathy. Apathy is a frequent symptom in people with neurocognitive disorders. It is characterized by a loss of motivation, reduced interest in activities, and decreased emotional engagement. Apathy strongly affects quality of life, social interactions, and participation in care, and current drug treatments have limited effectiveness. For this reason, non-pharmacological approaches are increasingly recommended. The SENS'REM program combines virtual reality with personalized multisensory stimulation (visual, auditory, olfactory and gustatory) to help participants relive meaningful autobiographical memories in an immersive and emotionally engaging environment. Each participant receives one session per week for six weeks. The content of the sessions is adapted to the individual life history of each participant. The primary objective of this study is to evaluate the feasibility of implementing this program in institutional settings, including recruitment, organization, technical aspects, and participant adherence. Secondary objectives include evaluating changes in apathy, quality of life, cognitive functioning, social engagement, participant satisfaction, and the tolerance of the intervention. The main hypothesis of the study is that a personalized multisensory virtual reality reminiscence program is feasible in nursing home and long-term care settings and may contribute to a reduction in apathy and an improvement in engagement and well-being among older adults with cognitive impairment. This pilot study will provide essential preliminary data to optimize the intervention and prepare a future larger comparative clinical trial.

The goal of this trial is to learn whether home-based robotic interventions can reduce apathy in people with cognitive decline. Apathy means reduced motivation, interest, or initiative in daily life. It is a common and distressing symptom in people with mild cognitive impairment (MCI) or dementia and can strongly affect both participants and their caregivers. This study will compare two different robotic interventions with standard occupational therapy. Researchers want to understand if these new technologies can help people become more engaged, motivated, and involved in everyday activities, and whether they also reduce stress and improve quality of life for caregivers. The main questions this study aims to answer are: * Do robotic interventions reduce apathy more than standard occupational therapy? * Are these robotic interventions easy to use and acceptable for people with cognitive impairment? * Do these interventions reduce caregiver stress and improve caregiver quality of life? Participants will be adults over 40 years of age with a diagnosis of mild cognitive impairment or dementia caused by a neurodegenerative disease, such as Alzheimer's disease, frontotemporal dementia, or dementia with Lewy bodies. All participants must show clinically relevant apathy and have a family member or caregiver who can support them during the study and answer questionnaires. Participants will be randomly assigned to one of three groups: * A telepresence robot group, where participants interact at home with a therapist through a remotely controlled robot that delivers personalized cognitive stimulation. * A social robot group, where participants interact at home with a humanoid robot that holds personalized conversations on topics of interest. * A control group receiving home-based occupational therapy, which is the current standard care for behavioral symptoms. Each intervention lasts six weeks and takes place in the participant's home. The robotic interventions are designed to fit into daily routines and can be adapted to the participant's abilities and preferences. Occupational therapy sessions focus on meaningful activities, environmental adaptations, and caregiver support. Participants will complete assessments at three time points: before the intervention, at the end of the six-week intervention, and eight weeks after the intervention ends. These assessments include interviews, questionnaires, and simple tasks to measure apathy, emotional responses, social interaction, and quality of life. Caregivers will also complete questionnaires about stress and daily burden. Researchers will also collect information about how often and how participants interact with the robots, such as how long conversations last and how engaged participants appear. These data will help researchers understand how robotic interactions relate to changes in apathy and behavior. This study aims to provide evidence on whether robotic technologies can be safely and effectively used at home to support people with cognitive impairment and apathy. The results may help develop new non-drug treatments and improve care options for people living with dementia and their caregivers.

This observational study investigates the use of Esketamine Intranasal Spray in patients with Treatment-Resistant Depression in Real-World Settings. The study aims to evaluate the clinical outcomes, including efficacy and safety, of esketamine treatment. It also explores predictors of treatment response, focusing on biological pathways such as genetics, neuroimaging, and psychophysical measures. Additionally, the study examines how esketamine impacts patients' life functioning, including social and occupational aspects. The goal is to better understand who benefits most from esketamine and how it affects daily life, to improve personalized care for patients with difficult-to-treat depression.

Parkinson's Disease (PD) is often accompanied by non-motor symptoms that make treatment more difficult. One such symptom is apathy (lack of motivation and emotion). There are no treatments for apathy in PD, and this remains a major unmet need in PD patients. One possible way to target apathy in PD patients is listening to music, which has been shown to help improve apathy in older adults. Little work has explored the mechanism in which music targets apathy. Thus, the goal of this study is to understand how music listening can impact the brain towards decreasing apathy in PD patients.

This study aims to observe the effects of daily personalized digital reminiscence sessions, conducted with the help of a digital conversational agent, and to determine whether these sessions lead to improvements in symptoms such as apathy and depression. The researchers therefore seek to observe whether this daily use can improve certain aspects of well-being, such as motivation, mood, sleep quality, quality of life, and engagement with the tool. The study also aims to assess whether simple reminders delivered via the application are sufficient to encourage regular use without external assistance. Participants will: * Use the reminiscence app for 25 days for 10-15 minutes. * Have a primary caregiver help personalize the app by sharing family memories, other relatives may optionally contribute in a private group. * Complete brief questionnaires at the start and during follow-up routine visits (for example, apathy and depression scales, sleep, and quality of life).

This clinical trial's goal is to evaluate if the IRL757 is safe and has a good tolerability in participants with Parkinson's disease and experiencing apathy (a lack of interest or motivation). In addition, the trial is aiming to learn if IRL757 has effects on the symptoms of Parkinson's disease. Researchers will compare the effects of IRL757 to a placebo (a look-alike substance that contains no drug). Participants who fit the study criteria will be treated with the study drug (either the active drug IRL757 or placebo) for 12 weeks and will visit the clinic at 5 defined timepoints for check-ups and tests. A follow-up call after the end of treatment will be done 4 weeks after the last study drug intake.

Reminiscence therapy is a non-invasive, non-pharmacological intervention that has been shown to improve cognition, mood, functional status, quality of life, and apathy in older adults. Group reminiscence therapy combines structured social engagement and recounting of personal stories that address both social connection (a risk factor for cognitive decline) and cognition. Life story club© (LSC) is an established, non-profit organization that provides virtual, group reminiscence therapy for older adults to reduce loneliness and promote a sense of belonging and has not been formally studied.

This study evaluates whether the combined treatment of methylphenidate and non-invasive brain stimulation, called intermittent theta burst stimulation, can effectively treat apathy in individuals with Alzheimer's disease or mixed AD/vascular dementia

The goal of this clinical trial is to learn whether 100HZ respiratory-gated vagus nerve stimulation (RAVANS) can improve the non-motor symptoms in people with Parkinson's disease (PD). It will also learn the safety of 100HZ RAVANS. The main questions it aims to answer are: Can 100HZ RAVANS improve apathy in people with PD? Did the participants have any side effects or safety issues when undergoing 100HZ RAVANS? Researchers compared 100HZ RAVANS with sham stimulation (low-dose stimulation of the same site and treatment parameters) to see if 100HZ RAVANS could improve non-motor symptoms in patients with PD. Participants will: Receive 100HZ RAVANS or sham stimulation for 2 weeks. Neuropsychological assessment, imaging and biological sample collection were conducted before and after the entire cycle.

Apathy is a common set of symptoms seen in many people following a stroke. Apathy occurs when a person has lost motivation, becomes withdrawn, and stops doing things that used to be important to them. Apathy has a large negative impact on a person's quality of life, and can also have a large impact the people who take care of them. There are currently no FDA-approved treatments to help with apathy, and other services like therapy may be difficult to access for people who have had a stroke. To address this problem, investigators are conducting a study to find out if a form of treatment called repetitive transcranial magnetic stimulation (rTMS) can be safe and helpful for people struggling with apathy after a stroke. This study will apply a new form of rTMS which can be delivered quickly to a part of the brain called the medial prefrontal cortex (mPFC). This study will help establish whether this treatment is safe, comfortable, and effective for people with apathy after a stroke, and will help researchers develop new forms of treatment.

The goal of this randomized controlled trial is to evaluate the potential of a customized digital cognitive training intervention to target aspects of brain function in apathy of late-life depression and reduce symptoms of apathy and related cognitive and behavioral deficits. The investigators hypothesize that 4 weeks of a customized digital cognitive training program will lead to changes in brain connectivity, apathy severity, and cognitive control performance.

Apathy is defined by quantitative decrease in goal-directed activity in comparison to the person's previous level of functioning. Apathy is a transnosographic symptom, prevalent in many neurological and psychiatric pathologies (specifically in schizophrenia and depression), and almost half of patients suffer from it. It is an important source of burden, affecting both personal and occupational life. Despite its high prevalence and negative consequences, no pharmacological or non-pharmacological treatments exist, the underlying mechanisms of apathy being poorly understood. The main aim of the present study is to advance in our knowledge of cognitive and neural mechanisms of apathy by using a multidimensional model of apathy, distinguishing three forms: executive, emotional and auto-activation/initiative. the investigators hypothesize, independently of the pathology (schizophrenia and depression), the existence of different cognitive deficits underlying each of the 3 subforms of apathy. Indeed, according to the predictions of Levy and Dubois' model (2006), executive disorders underlie the cognitive form of apathy. It may be related to lesions of the dorsolateral prefrontal cortex and the cognitive territory of the basal ganglia. Emotional apathy could be due to motivational disorder. Dysfunctions or lesions in the orbital and medial prefrontal cortex and limbic territories of the basal ganglia may underlie this. Finally, the initiative form, may be a mixed form, with both motivational and executive difficulties. Lesions or dysfunctions may affect both the cognitive and limbic territories of the basal ganglia or the anterior cingulate cortex.

Apathy is a disabling neuropsychiatric symptom marked by reduced goal-directed behavior, including diminished interest, motivation, emotional expression, and social engagement. Though not formally defined in the DSM-V, apathy is common in several neurological and psychiatric disorders and significantly affects quality of life. In Parkinson's Disease (PD), it affects about 40% of patients and is associated with increased caregiver burden, reduced functional ability, and nearly threefold higher mortality. PD affects over 680,000 Americans today and is projected to impact more than 1.2 million by 2030. It presents with both motor symptoms (e.g., bradykinesia, tremor, rigidity) and non-motor symptoms like depression, anxiety, and apathy. While motor symptoms are often managed with dopaminergic medications and deep brain stimulation (DBS) targeting motor regions (e.g., subthalamic nucleus, globus pallidus internal), apathy typically persists or worsens following these treatments. No FDA-approved or consistently effective treatments exist for apathy in PD. Dopamine agonists may help but have side effects that limit long-term use. SSRIs and cholinesterase inhibitors may be tried for co-occurring depression or cognitive decline, but they are not indicated for apathy and can worsen symptoms or cause adverse effects in PD. This protocol proposes targeting apathy in PD using DBS of the ventral capsule/ventral striatum (VC/VS), a region involved in reward processing and goal-directed behavior. VC/VS DBS is FDA-approved under a Humanitarian Device Exemption for OCD and has shown promise in treating depression, addiction, and other disorders involving motivational deficits. Neuroimaging and preclinical models strongly implicate this region in the regulation of goal-directed behavior, reward sensitivity, and cognitive control-mechanisms disrupted in apathy. Stimulating VC/VS may improve motivation through fibers connected to orbitofrontal and anterior cingulate cortices (reward sensitivity) and dorsal prefrontal regions (cognitive control). Support for this approach comes from a case report where a patient with PD and OCD received both STN and VC/VS DBS. In addition to motor and OCD symptom improvement, the patient showed a significant reduction in apathy. Apathy worsened when stimulation ceased and improved again when resumed, suggesting a causal relationship. VC/VS DBS was safe, did not impair motor symptoms, and appeared to enhance motivation. This study aims to test the safety and efficacy of VC/VS DBS for apathy in PD. Building on extensive animal, imaging, and clinical data, it addresses a major unmet need using an existing DBS platform. The approach is supported by established neurocircuitry, prior clinical experience with VC/VS targeting, and early evidence suggesting potential benefit. It does not duplicate prior studies but extends DBS to a new, underserved indication within PD.

The goal of this clinical trial is to identify reliable markers of apathy in elderly subjects with bipolar disorder, age between 70 and 85 years, in order to accurately identify subjects at high risk of progressing to dementia by measuring motor activity (actimetrics), recorded language and analysing brain changes (MRI). Actimetry is the measurement and recording of body movements using an actimeter. This device is worn on the wrist and contains sensors capable of measuring and recording all movements, including those of very low intensity. An automated speech analysis using artificial intelligence is used to detect low-intensity anomalies, and we want to test whether individual differences correspond to individual differences in brain anatomy and function. Researchers will compare elderly subjects with bipolar disorder and healthy volunteer, age between 70 and 85 years. Participants will be asked to: * Perform an MRI * Complete 3 cognitive tests: verbal memory, verbal fluency and an emotional storytelling task, in which you will be asked to describe a memory orally using positive, negative and neutral emotions. * wear an actimeter on your wrist for 4 days.

The aim of this study is to investigate the behavioural effects and neural correlates of increasing serotonin levels in healthy volunteers, through a 7-day course of the SSRI escitalopram, on an effort-based decision-making task measuring self-benefiting and prosocial behaviours.

This study is looking to determine if Lumateperone improves motivation in patients with schizophrenia or schizoaffective disorders who show high levels of apathy as judged by AES-C-Apathy (Apathy Evaluation Scale - Clinician - Apathy) assessment and to examine a possible correlation between improvement in apathy scores and changes in elements of the PANSS (Positive and Negative Syndrome Scale) due to treatment with Lumateperone.

In its 2012's release guideline on therapy for schizophrenia, the EMA joined the FDA to acknowledge primary and persistent negative symptoms (PNS) as an unmet need in the treatment of schizophrenia. Functional brain imaging studies showed a correlation between NS and reduced perfusion in the left dorsolateral prefrontal cortex (L-DLPFC). Pre-frontal activation (PFA) using repetitive transcranial magnetic stimulation (rTMS) significantly improve PNS (meta-analyses: effect size SMD = 0.55, ΔPANSS-N = -2.5). Yet schizophrenia is likely to gather many different natural entities of distinct pathophysiological mechanisms. Pursuing a one-size-fits-all approach will not adapt to this diversity and might account for inconsistencies in the results. Progressive periodic catatonia (PPC) is a rare psychotic phenotype (0.1 - 0.5 ‰) which has been shown to be longitudinally stable (30-years follow-up) and consistent within families (about 1 third of first-degree relatives are affected). The core of this phenotype is a disintegration of psychomotor processes which progresses with each relapse, resulting in a "deficit state", i.e., PNS, responsible for most social and occupational disabilities. The investigators and others reported PPC to come with hyper-perfusions in premotor cortices compared to controls or non-PPC chronic psychoses (nPPC). These hyper-perfusions discriminate PPC from nPPC or depressive patients (Sensitivity = 82%; Specificity = 95%). Last, in independent proof-of-principle studies the investigators and others have shown that premotor inhibition (PMI) using rTMS significantly improved PNS in PPC and that the most dramatic improvements followed personalized accelerated rTMS protocols (5 days of rTMS; CGI-improvement = 2 which is equivalent to ΔPANSS-N = -10; lasting \> 1 month - vs virtually no change for PFA). The efficacy index was very good (no side effects). the investigators hypothesize that: (1) in PPC, add-on personalized premotor inhibition (PMI) is more effective in reducing PNS than L-DLPFC activation (PFA); (2) patient stratification is relevant as personalized PMI will not be as effective in the nPPC group (even expected to be less effective than PFA).

Apathy is one of the most common behavioral symptoms of Parkinson's disease. Patients with apathy show diminution in motivation and goal-directed behaviors, which is a fundamental aspect of human functioning, affecting dependency and quality of life. Although apathy is thought to be potentially treatable currently there are no effective treatments for apathy. Given the higher incidence of medical and psychiatric comorbidities, the Veterans Affairs health system represents a unique population for which medication response may be different from the general population. This study aims to evaluate if a medication that has already been proven to be useful in Alzheimer's disease patients with apathy, could be helpful in Parkinson's disease as well as decreasing its debilitating consequences and reducing patients' dependency on caregivers, providing well-deserved relief to patients and their loved ones.