The acute and chronic effects of VNS stimulation on various on the autonomic nervous, cardiovascular, immune, and metabolic systems will be compared from noninvasive and minimally invasive physiological recordings and blood draws at various time points throughout the study. These interventions and assessments will be performed in individuals 18 years of age and older who are implanted with a VNS device, which consists of patients who have been diagnosed with drug resistant epilepsy or major depressive disorder. The REVEAL study is not a treatment study; its primary objective is to scientifically investigate the contributing roles of efferent versus afferent vagus nerve modulation of multiple peripheral organs and their dependence on stimulation parameters, in which participants are those who have been implanted with a VNS device be receive standard of care treatment for their epilepsy or depressive disorder.

Inclusion Criteria:

Cohort 1a (p-VNS): Inclusion Criteria for Participants With Major Depressive Disorder That Have a Previously Implanted VNS Device

• Participant must be at least 18 years old.
• Participant must have the capacity to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
• Participant must be enrolled in an active health insurance plan that will cover the costs associated with standard health care services and injuries.
• Participant must have been previously implanted with a VNS device for the clinical indication of Major Depressive Disorder (MDD).
• Participant must be able and willing to complete the evaluations and procedures described in the study protocol.
• Participant's usage of concomitant medications must be stable for two months preceding study enrollment and the participant must be able and willing to maintain stable usage of any concomitant medications from the day of enrollment through the completion of Study Visit 2.
• Participant that is of childbearing potential must be adequately protected from conception or willing to use an acceptable method of birth control over the entire study duration (acceptable birth control includes abstinence, barrier methods, hormonal methods, sterilization and fertility awareness).

Cohort 1b (n-VNS): Inclusion Criteria for Participants With Major Depressive Disorder That Will Receive a Newly Implanted VNS Device

• Participant must be at least 18 years old.
• Participant must have the capacity to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
• Participant must be enrolled in an active health insurance plan that will cover the costs associated with standard health care services and injuries.
• Participant has a diagnosis of chronic (≥ 2 years) or ≥ 4 recurrent depressive episodes as defined by DSM-5 criteria documented using the MINI criteria and psychiatric medical record review. Participant must have VNS therapy clinically indicated.
• Participant has not had an adequate response to four or more adequate antidepressant treatments from at least two different antidepressant treatment categories in the current depressive episode according to the Antidepressant Treatment History Form (ATHF).
• Participant must have a score on the baseline administration of the Montgomery-Åsberg Depression Rating Scale (MADRS) of ≥ 22.
• Participant must be able and willing to complete the evaluations and procedures described in the study protocol.
• Participant's usage of concomitant medications must be stable for two months preceding study enrollment and the participant must be able and willing to maintain stable usage of any concomitant medications from the day of enrollment through the completion of Study Visit 2.
• Participant that is of childbearing potential must be adequately protected from conception or willing to use an acceptable method of birth control over the entire study duration (acceptable birth control includes abstinence, barrier methods, hormonal methods, sterilization and fertility awareness).

Cohort 2a (p-VNS): Inclusion Criteria for Participants With Drug Resistant Epilepsy That Have a Previously Implanted VNS Device

• Participant must be at least 18 years old.
• Participant must have the capacity to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
• Participant must be enrolled in an active health insurance plan that will cover the costs associated with standard health care services and injuries.
• Participant must have been previously implanted with a VNS device for the clinical indication of drug resistant epilepsy.
• Participant has not had demonstrable benefit from the implanted VNS device in terms of epilepsy (seizure frequency or seizure severity) or related epilepsy comorbidities (mood, cognition, quality of life), with no definite improvement or suboptimal improvement in seizure control.
• Apart from epilepsy, the participant should be medically and neurologically stable.
• Participant must be able and willing to complete the evaluations and procedures described in the study protocol.
• Participant's usage of concomitant medications must be stable for two months preceding study enrollment and the participant must be able and willing to maintain stable usage of any concomitant medications from the day of enrollment through the completion of Study Visit 2.
• Participant that is of childbearing potential must be adequately protected from conception or willing to use an acceptable method of birth control over the entire study duration (acceptable birth control includes abstinence, barrier methods, hormonal methods, sterilization and fertility awareness).

Cohort 2b (n-VNS): Inclusion Criteria for Participants With Drug Resistant Epilepsy That Will Receive a Newly Implanted VNS Device

• Participant must be at least 18 years old.
• Participant must have the capacity to provide written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization.
• Participant must be enrolled in an active health insurance plan that will cover the costs associated with standard health care services and injuries as well as the costs associated with the VNS implantation surgery.
• Participant is diagnosed with drug resistant epilepsy, with continuing seizures despite adequate trials of at least 2 appropriate antiseizure drugs (ASDS) with therapeutic serum concentrations as per the International League Against Epilepsy (ILAE) Commission on Therapeutic Strategies.
• Apart from epilepsy, the participant should be medically and neurologically stable.
• Participant must be able and willing to complete the evaluations and procedures described in the study protocol.
• Participant's usage of concomitant medications must be stable for two months preceding study enrollment and the participant must be able and willing to maintain stable usage of any concomitant medications from the day of enrollment through the completion of Study Visit 2.
• Participant that is of childbearing potential must be adequately protected from conception or willing to use an acceptable method of birth control over the entire study duration (acceptable birth control includes abstinence, barrier methods, hormonal methods, sterilization and fertility awareness).
• Participant has been informed of his or her eligibility for resective surgery as a potential alternative to receiving, as standard of care, the VNS device that is required for participation in this study, if such surgery is a reasonable option.

Exclusion Criteria:

Cohort 1a (p-VNS): Exclusion Criteria for Participants With Major Depressive Disorder That Have a Previously Implanted VNS Device

• Participant has a prior implantable stimulation device, other than a VNS device for the clinical indication of Major Depressive Disorder (MDD).
• Participant currently uses or is expected during the study to use short-wave diathermy, microwave, diathermy, or therapeutic ultrasound diathermy.
• Participant is judged by the investigator to be acutely suicidal (e.g. has made specific plans or preparations to commit suicide or as indicated by the Sheehan Suicidality Tracking Scale) within the last 30 days prior to study enrollment.
• Participant has made a suicide attempt within the previous 6 months from study enrollment.
• Participant has a history of one or more schizophrenia-spectrum or other psychotic disorders including schizophrenia, schizoaffective disorder, delusional disorder, or a current or lifetime major depressive episode that includes psychotic features (commonly referred to as psychotic depression) according to the MINI criteria.
• Participant has a history of significant borderline or severe personality disorder as determined by clinical judgment.
• Participant has an active primary diagnosis of obsessive-compulsive, eating, or post-traumatic stress disorder based on the MINI criteria.
• Participant has a diagnosis of Substance Use Disorder as defined by DSM-5 without sustained remission of 12 months or longer.
• Participant has a presence of any type of dementia, major neurocognitive disorder, or cognitive or psychiatric deficit as determined by clinical judgment.
• Participant has a history of rapid cycling bipolar disorder I or II.
• Participant currently receives treatment with another investigational device or investigational drug other than the REVEAL study, or has participated in another drug or device trial within the preceding 30 days before enrollment.
• Participant is not able or willing to use their dominant arm, or either upper arm circumference is greater than 50 cm.
• Participant does not speak English.
• Any other clinical reasons deemed by the investigators of the study in which the participant would not be an appropriate candidate for the study, such as peripheral vascular disease, Raynaud's phenomenon, orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), uncontrolled obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or uncontrolled diabetes.

Cohort 1b (n-VNS): Exclusion Criteria for Participants With Major Depressive Disorder That Will Receive a Newly Implanted VNS Device

• Participant has a prior implantable stimulation device.
• Participant currently uses or is expected during the study to use short-wave diathermy, microwave, diathermy, or therapeutic ultrasound diathermy.
• Participant is judged by the investigator to be acutely suicidal (e.g. has made specific plans or preparations to commit suicide or as indicated by the Sheehan Suicidality Tracking Scale) within the last 30 days prior to study enrollment.
• Participant has made a suicide attempt within the previous 6 months from study enrollment.
• Participant has a history of one or more schizophrenia-spectrum or other psychotic disorders including schizophrenia, schizoaffective disorder, delusional disorder, or a current or lifetime major depressive episode that includes psychotic features (commonly referred to as psychotic depression) according to the MINI criteria.
• Participant has a history of significant borderline or severe personality disorder as determined by clinical judgment.
• Participant has an active primary diagnosis of obsessive-compulsive, eating, or post-traumatic stress disorder based on the MINI criteria.
• Participant has a diagnosis of Substance Use Disorder as defined by DSM-5 without sustained remission of 12 months or longer.
• Participant has a presence of any type of dementia, major neurocognitive disorder, or cognitive or psychiatric deficit as determined by clinical judgment.
• Participant has a history of rapid cycling bipolar disorder I or II.
• Participant currently receives treatment with another investigational device or investigational drug other than the REVEAL study, or has participated in another drug or device trial within the preceding 30 days before enrollment.
• Participant with vocal cord paralysis.
• Participant is not able or willing to use their dominant arm, or either upper arm circumference is greater than 50 cm.
• Participant does not speak English.
• Any other clinical reasons deemed by the investigators of the study in which the participant would not be an appropriate candidate for the study, such as peripheral vascular disease, Raynaud's phenomenon, orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), uncontrolled obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or uncontrolled diabetes.

Cohort 2a (p-VNS): Exclusion Criteria for Participants With Drug Resistant Epilepsy That Have a Previously Implanted VNS Device

• Participant has demonstrable benefit from implanted VNS device in terms of epilepsy (seizure frequency or seizure severity) or epilepsy comorbidity (mood, cognition, or quality of life), with seizure freedom or clinical benefit.
• Participant has a prior implantable stimulation device, other than a VNS device for the clinical indication of refractory focal Epilepsy.
• Participant currently uses or is expected during the study to use short-wave diathermy, microwave, diathermy, or therapeutic ultrasound diathermy.
• Participant has been hospitalized for a psychiatric condition within the preceding 6 months or has had a history of psychosis within the preceding two years (excluding postictal psychosis).
• Participant has experienced unprovoked status epilepticus in the preceding year.
• Participant has a diagnosis of Substance Use Disorder as defined by DSM-5 without sustained remission of 12 months or longer.
• Participant currently receives treatment with another investigational device or investigational drug other than the REVEAL study, or has participated in another drug or device trial within the preceding 30 days before enrollment.
• Participant is not able or willing to use their dominant arm, or either upper arm circumference is greater than 50 cm.
• Participant does not speak English.
• Any other clinical reasons deemed by the investigators of the study in which the participant would not be an appropriate candidate for the study, such as peripheral vascular disease, Raynaud's phenomenon, orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), uncontrolled obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or uncontrolled diabetes.

Cohort 2b (n-VNS): Exclusion Criteria for Participants With Drug Resistant Epilepsy That Will Receive a Newly Implanted VNS Device

• Participant has a prior implantable stimulation device.
• Participant currently uses or is expected during the study to use short-wave diathermy, microwave, diathermy, or therapeutic ultrasound diathermy.
• Participant has been hospitalized for a psychiatric condition within the preceding 6 months or has had a history of psychosis within the preceding two years (excluding postictal psychosis).
• Participant has experienced unprovoked status epilepticus in the preceding year.
• Participant has a diagnosis of Substance Use Disorder as defined by DSM-5 without sustained remission of 12 months or longer.
• Participant currently receives treatment with another investigational device or investigational drug other than the REVEAL study, or has participated in another drug or device trial within the preceding 30 days before enrollment.
• Participant with vocal cord paralysis.
• Participant is not able or willing to use their dominant arm, or either upper arm circumference is greater than 50 cm.
• Participant does not speak English.
• Any other clinical reasons deemed by the investigators of the study in which the participant would not be an appropriate candidate for the study, such as peripheral vascular disease, Raynaud's phenomenon, orthostatic hypotension (OH), postural orthostatic tachycardia syndrome (POTS), uncontrolled obstructive sleep apnea (OSA), chronic obstructive pulmonary disease (COPD), or uncontrolled diabetes.