Antibody-mediated NMDA Receptor Encephalitis: Symptoms, Biomarkers, and Mechanisms of the Prolonged Recovery Stage

Not Applicable

Recruiting

• Conditions: Anti-NMDA Receptor Encephalitis
• Interventions: Behavioral: Remote cognitive rehabilitation program

• Registration Number: NCT06183788
• Lead Sponsor: Fundacion Clinic per a la Recerca Biomédica

Brief Summary

The encephalitis mediated by antibodies against the NMDA receptor (NMDARe) predominantly affects young adults and children resulting in severe neurologic and psychiatric deficits. After overcoming the acute stage, patients are left with long-lasting behavioral, cognitive, and psychiatric alterations with important socio-family-economical implications. Here investigators postulate that a better knowledge of this stage will improve treatment decisions and outcome.

In Aim 1, the post-acute stage will be clinically characterized, tools to remotely follow cognitive, behavioral and psychiatric deficits will be provided, and the impact of cognitive rehabilitation will be assessed.

In Aim 2, biomarkers (autoimmune, inflammatory, neuronal injury) will be identified as signatures of the acute and post-acute stages.

In Aim 3, a mouse model of NMDARe will be used to determine the underlying mechanisms and treatment of the postacute stage.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-01-16
• Study First Submitted: 2023-05-19
• Study First Submitted QC: 2023-12-13
• Study First Posted: 2023-12-28
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-03
• Last Update Posted: 2024-05-06
• Primary Completion: 2025-01-01
• Study Completion: 2025-11-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Patients ≥12 years old with NMDARe in the post-acute stage of the disease;
• ≤6 months from hospital discharge (acute phase)

Exclusion Criteria (one of the following):

• Inability to obtain informed consent;
• inability to travel to the center.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Anti-NMDARe patients with remote cognitive rehabilitation	Remote cognitive rehabilitation program	Participants of a prospective cohort in post-acute phase of the Antibody-mediated NMDA Receptor Encephalitis that will received a behavioral treatment.

Primary Outcome Measures

Name	Time	Method
Gender	18 months	Male or female
Allergies	18 months	List of allergies of each participant
Verbal working memory	18 months	Verbal Working Memory: Working Memory Index (WMI) from WAIS-IV.; - Range of WMI: from 50 to 150. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Age	18 months	Age measured in years
Treatments	18 months	All treatments in which the participant is being involved.
Handedness	18 months	Right- or Left-handed
General medical history	18 months	Description of the most important issues compiled in the general medical history of the participant
Functional status	18 months	Functional status according to Modified Rankin Scale (mRS); Modified Rankin Scale: - Range: from 0 points (no symptoms) to 6 points (dead).
Intelligence Quotient	18 months	Estimated through General Ability Index (GAI; from Weschler Adult Intelligence Scale - IV (WAIS-IV).; This index is obtained through Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI).; * Range of GAI: from 40 to 160. Higher is better.; * Range of VCI: from 50 to 150. Higher is better.; * Range of PRI: from 50 to 150. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Short-term verbal memory	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Short-term memory free recall: range: 0 to 15. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Verbal discrimination memory	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Discrimination index of word-list: False positives + omissions of recognition between 44 total words to recognize. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Visual recognition memory	18 months	Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R); - Figure Recognition: range: from 0 to 6. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
TMT-A	18 months	Trail Making Test part A (TMT-A): - Time in seconds: from 0 to infinity.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Symptoms related to NMDARe	18 months	Detailed description of symptoms experienced before, during and after the post-acute phase of NMDARe.
Visual working memory	18 months	Visual Working Memory: Spatial location subtest from Weschler Memory Scale - IV (WMS-IV).; - Range of Spatial Location subtest: from 0 to 32. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Long-term verbal memory	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Long-term memory free recall: range: 0 to 15. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Delayed visual memory	18 months	Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R); - Delayed visual memory: range: from 0 to 12. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Visuospatial skills - children	18 months	Assessed by Arrows subtest of NEPSY-2 battery; - Range: from 0 to 20; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Stroop test - word subtest	18 months	- Words: words read in 45 seconds; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Phonological loop	18 months	Assessed by Forward order span of Digit span subtest from WAIS-IV.; - Range: from 0 to 9; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Proactive interference verbal memory	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Interference list: range: 0 to 15. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Verbal retention memory	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Retention index: percentatge of Long-term memory free recall between Short-term memory free recall. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Visual retention memory	18 months	Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R); - Retention index: percentatge of Long-term memory free recall between the Higher punctuation at Trial 2 or 3. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Visuospatial skills	18 months	Number location subtest of the Visual-Object Spatial and Perceptual battery.; - Range: from 0 to 10; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
HRT ISI Change - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Hit Reaction Time Inter-Stimulus Interval Change (HRT ISI Change) indicates the change in mean response speed at various ISIs.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Verbal learning	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Total learning: range: from 0 to 80. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Visual discrimination memory	18 months	Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R); - Discrimination index: figure recognized minus false positives. Range: from -6 to 6. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Processing speed	18 months	Processing speed Index (PSI; from Weschler Adult Intelligence Scale - IV (WAIS-IV).; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Naming	18 months	Assessed by: Boston Naming Test (BNT); - Total correct: from 0 to 60; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Naming with cues	18 months	Assessed by: Boston Naming Test (BNT); - Total correct with phonemic cue: from 0 to 60
Latency in naming	18 months	Assessed by: Boston Naming Test (BNT); - Time to complete test in seconds
Phonemic fluency	18 months	Number of words started by letter "M" recalled in 1 minute: Range: from 0 to infinity. (Test Barcelona-Revised) (for ADULTS) Number of words started by letter "P" recalled in 1 minute + number of words started by letter "M" in 1 minute: range: from 0 to infinity (NEPSY-II) (for CHILDREN).; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
HRT - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Hit Reaction Time (HRT) is the mean response speed of correct responses from the whole administration.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Variability- CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; The amount of variability that the patient showed in 18 separate segments of the administration in relation to their own overall Hit Reaction Time Standard Deviation (HRT-SD).; It is a measure of response consistency and a "within respondent" measure".; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
HRT Block Change - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Hit Reaction Time Block Change indicates the change in mean response speed across blocks.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Sleep microstructure - Sleep efficiency	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Sleep efficiency: based on total study time and total sleep time
Verbal recognition memory	18 months	Assessed by: Adults: España - Complutense Auditory-Verbal Learning Test (Test de Aprendizaje Verbal España - Complutense; TAVEC); or Infants: España - Complutense Auditory-Verbal Learning Test for Children (Test de Aprendizaje Verbal España - Complutense Infantil; TAVECI); - Word-list Recognition: range: 0 to 15. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Immediate visual memory	18 months	Assessed by: Brief Visuospatial Memory Test - Revised (BVMT-R); - Immediate visual memory: range: from 0 to 36. Higher is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
TMT-B	18 months	Trail Making Test part B (TMT-B): - Time in seconds: from 0 to infinity.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Detectability - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Measures the respondent's ability to differentiate non-targets (i.e. the letter X) from targets (i.e. all other letters).; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Omissions - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Result from a failure to respond to targets.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Sleep microstructure - Time in stage N1	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Time in stage N1: minutes
Sleep microstructure - Time in stage N2	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Time in stage N2: minutes
Sleep microstructure - Number of arousals	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Number of arousals (total)
Semantic fluency	18 months	Number of name of animals recalled in 1 minute: range: from 0 to infinity. (Test Barcelona - Revised) (for ADULTS) Number of name of animals recalled in 1 minute + number of name of food and drinks recalled in 1 minute: from 0 to infinity (NEPSY - II) (for CHILDREN); Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Stroop test - color subtest	18 months	- Colour: colours distinguished in 45 seconds.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
HRT-SD - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Hit Reaction Time Standard Deviation (HRT-SD) is a measure of response speed consistency during the entire administration.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Prensence of psychiatric symptoms or disorders in presential assessments	18 months	Number of participants with psychiatric symptoms/disorders following DSM-IV-TR guidelines (psychotic symptoms, symptoms of depression, symptoms of mania, global functioning).
Sleep microstructure - First epoch of REM	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - First epoch of REM: minutes
Sleep microstructure - Delta arousals	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - "Delta arousals"?: yes, no or unknown
Stroop test - word-color subtest	18 months	- Word-colour: colours distinguished in 45 seconds.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Comissions - CPT3	18 months	Assessed by Continuous Performance Test - 3rd Version.; Comissions are made when responses are given to non-targets.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Sleep microstructure - Total study time	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Total sleep time: minutes
Sleep microstructure - Total sleep time	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Total sleep time: minutes
Sleep microstructure - Time in stage N3	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Time in stage N3: minutes
Sleep microstructure - Time in stage R	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Time in stage R: minutes
Sleep microstructure - First epoch of N1	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - First epoch of N1: minutes
Sleep microstructure - First epoch of N2	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - First epoch of N2: minutes
Sleep microstructure - First epoch of N3	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - First epoch of N3: minutes
Sleep microstructure - Time to sleep onset	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Time to sleep onset: minutes
Sleep microstructure - REM/NREM time ratio	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - REM/NREM time ratio
Sleep microstructure - Direct transition from N3 to W	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Direct transition from N3 to W: yes or no
Sleep microstructure - Wake after sleep	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Wake after sleep: hour
Adherence to cognitive treatment - 6 months	6 months	Number of sessions performed in 6 months
Sleep microstructure - Arousal Index	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Arousal Index
Sleep microstructure - Confusional arousals	18 months	It will be adapted to patient's sleep habits (\~23:00 to 07:30) using a digital polygraph (Deltamed). This includes EEG in 43 scalp channels + 11 channels for electrooculography, electrocardiography, electromyography, and audiovisual recording (sampling rate 256 Hz). Sleep stages will be scored manually (AASM criteria) using 30-s epochs, with modifications depending on sleep alterations, as reported.; Parameters: - Confusional arousals: Yes or No
Adherence to cognitive treatment - 9 months	9 months	Number of sessions performed in 9 months
Adherence to cognitive treatment - 12 months	12 months	Number of sessions performed in 12 months
Vision condition	18 months	Studied by optometer

Secondary Outcome Measures

Name	Time	Method
Neurofilament light chain (NfL) levels in acute stage	18 months	Signature of molecular biomarkers in the acute stage
Cell immunophenotyping - proportion of CD8+CD45RO+	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD8+CD45RO+.
Cell immunophenotyping - proportion of plasmablasts	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of plasmablasts.
Cell immunophenotyping - proportion of NK cells	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of NK cells.
Neurofilament light chain (NfL) levels in post-acute stage	18 months	Signature of molecular biomarkers in the post-acute stages
Cell immunophenotyping - proportion of CD8	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD8.
Cell immunophenotyping - proportion of B naive (IgM+IgD+CD27-)	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of B naive (IgM+IgD+CD27-).
Cell immunophenotyping - proportion of B memory (IgD-)	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of B memory (IgD-).
Cell immunophenotyping - proportion of CD4	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD4.
EEG: seizures	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Seizures: yes or no
Long-term verbal memory - remote assessment	18 months	Assessed by: Long-term verbal memory subtest from Rey Auditory Verbal Learning Test (RAVLT); - Range: 0 - 15; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Immune/inflammatory signaling-target gene expression pathways	18 months	Whole blood/CSF will be collected using PAXgene® Blood RNA Tubes (Qiagen) shipped to the centers. Blood from healthy subjects and CSF from patients with normal pressure hydrocephalus will serve as controls.; Total RNA will be extracted using PAXgene® Blood RNA Kit (Qiagen). RNA samples are quantified using Qubit 2.0 Fluorometer (Life Technologies) and RNA integrity is determined with Agilent 2100 Bioanalyzer (Agilent Technologies).; Expression levels of 44 genes related to immune/inflammatory (or cytokine) pathways will be measured with the nCounter® Digital Analyzer (NanoString).; The raw copy number of mRNA transcripts of each gene will be standardized (stdGene) using the geometric mean of the 4 housekeeping genes for each subject.
EEG: time asleep	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Time asleep: percentage
EEG: slowing	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - EEG slowing: yes or no
EEG: Changes with hyperventilation	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Changes with hyperventilation: yes or no
Short-term verbal memory - remote assessment	18 months	Assessed by: Short-term verbal memory subtest from Rey Auditory Verbal Learning Test (RAVLT); - Range: 0 - 15; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Cell immunophenotyping - proportion of CD8+CD45RA+	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD8+CD45RA+.
Cell immunophenotyping - proportion of iNKT	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of iNKT.
Cell immunophenotyping - proportion of CD19	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of CD19.
Cell immunophenotyping - proportion of regulatory B cells	18 months	Whole blood/CSF obtained in a EDTA tube will be analyzed in a FACS Canto II cytometer to assess the proportion of regulatory B cells.
MRI	18 months	It will be conducted on a 3 Tesla Prisma scanner using a 32-channel head coil. Scanning takes \~50 min including 3D T1-weighted in sagittal plane; T2\*axial EPI; axial diffusion weighted EPI; 3D sagittal FLAIR; resting state functional MRI and glutamate and H2O univoxel spectroscopy in dorsolateral prefrontal cortex and hippocampus. There is no contrast used for the MRI scans; Outcome for MRI is normal or abnormal. Investigators will review all MRI sequences and determine if the MRI is abnormal and then describe the abnormality or abnormalities seen.
EEG: normalcy	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; - Normalcy: yes or no.
EEG: time awake	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Time awake: percentage
EEG: time in drowsiness	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Time in drowsiness: percentage
Verbal learning - remote assessment	18 months	Assessed by: Total learning List A subtest from Rey Auditory Verbal Learning Test (RAVLT); - Range: 0 - 75; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
EEG: epileptiform activity	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Epileptiform activity: yes or no
Verbal working memory - remote assessment	18 months	Assessed by: Digit subtest from WAIS-IV: obtained by Forward order, indirect order, increasing order subtests.; - Range: 0 - 48; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Proactive interference verbal memory - remote assessment	18 months	Assessed by: List B subtest from Rey Auditory Verbal Learning Test (RAVLT); - Range: 0 - 15; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Verbal discrimination memory - remote assessment	18 months	Assessed by: Verbal discrimination memory subtest from Rey Auditory Verbal Learning Test (RAVLT); - Range: 0 - 1; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Complex figure copy - remote assessment	18 months	Assessed by: Precision in the copy of the Rey-Osterrieth Complex Figure: - Range: 0-36; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Orientation in space - remote assessment	18 months	Assessed by: Orientation in space subtest from Test Barcelona - Revised.; - Range: 0 -5
EEG: Changes with Intermittent Light Stimulation	18 months	It will include standard clinical EEG protocol (43 channels, 512 Hz18) (primary variables), and EEG reactivations of memories prior to new trials (secondary variables) while participants perform WM tasks, which will be synchronized with the task software in a laptop. The memory content from alpha power across electrodes will be related to the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Performances of the subjects produces a reactivation of memory prior to new trials while participants perform working memory tasks, and relate the decoding accuracy in different task periods to disease treatment and recovery and to behavioral parameters (WM precision, serial biases).; Parameters: - Changes with Intermittent Light Stimulation: yes or no
Time - Complex figure copy - remote assessment	18 months	Assessed by: Time to perform the copy of the Rey-Osterrieth Complex Figure: seconds; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
5DT Choosing - remote assessment	18 months	Assessed by: Choosing subtest from 5 digit test: time; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
5DT Switching - remote assessment	18 months	Assessed by: Switching subtest from 5 digit test: time; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Time in Naming - remote assessment	18 months	Assessed by: Boston Naming Test (BNT): time to complete
Verbal recognition memory - remote assessment	18 months	Assessed by: Verbal recognition memory list subtest from Rey Auditory Verbal Learning Test (RAVLT); - Range: 0 - 15; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Type - Complex figure copy - remote assessment	18 months	Assessed by: Type of copy of the Rey-Osterrieth Complex Figure: - Range: 1 to 4
5DT Lecture - remote assessment	18 months	Assessed by: Lecture subtest from 5 digit test: time; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
SWM Double Errors - remote assessment	18 months	SWM Double Errors: The number of times a subject commits an error that is both a within error and a between error. Calculated across all assessed four, six and eight token trials.; Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 0 - 147. Lower is better.
ERTTHD - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total Hits Disgust: The total number of times the subject correctly selected the emotion 'Disgust'. Calculated across all assessed trials.; - Range: 0 - 15 . Higher is Better.
ERTTFAH - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total False Alarms Happiness: The total number of times the subject incorrectly selected the emotion 'Happiness'. Calculated across all assessed trials.; - Range: 0 - 75 . Lower is Better.
ERTUHRF - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Unbiased Hit Rate Fear: The unbiased hit rate ensures that recognition accuracy of the Fear emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Fear trials only.; - Range: 0 to 1. Higher is better.
Slow-wave rate of growth during slow-wave sleep period	18 months	This is quantified from EEG recorded during sleep, by detecting individual slow-waves and estimating their strength, and then computing the rate of growth of this strength in the first slow-wave periods in the night. We expect the rate of growth of slow waves to increase as patients improve.
Orientation in time - remote assessment	18 months	Assessed by: Orientation in time subtest from Test Barcelona - Revised.; - Range: 0 - 5; Higher is better.
5DT counting - remote assessment	18 months	Assessed by: Counting subtest from 5 digit test: time; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
IEDEEDS - remote assessment	18 months	IED EDS Errors: The number of times that the subject failed to select the stimulus compatible with the current rule on the stage where the extra-dimensional shift occurs. This is a measure of the subject's ability to shift attentional set.; Assessed by: Intra-Extra Dimensional test from CANTAB battery.; - Raw score range: 0 - 50. Lower is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
SWM Total Errors - remote assessment	18 months	SWM Total Errors: The total number of times a box is selected that is certain not to contain a token and therefore should not have been visited by the subject, i.e. between errors + within errors - double errors. Calculated across all assessed four, six and eight token trials.; Assessed by: Spatial Working Memory test from CANTAB battery.; - Range: 0 - 157. Lower is better
SWM Between Errors - remote assessment	18 months	SWM Between Errors: The number of times the subject incorrectly revisits a box in which a token has previously been found. Calculated across all assessed four, six and eight token trials.; Assessed by: Spatial Working Memory test from CANTAB battery: - Raw score range: 0 - 153. Lower is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
ERTTHH - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total Hits Happiness: The total number of times the subject correctly selected the emotion 'Happiness'. Calculated across all assessed trials.; - Range: 0 - 15 . Higher is Better
Visuospatial skills - remote assessment	18 months	Assessed by: Benton Judgment of Line Orientation Test (JLO): - Range: 0 to 30; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Short-term visual memory - remote assessment	18 months	Assessed by: Short term memory subtest of the Rey-Osterrieth Complex Figure: - Range: 0 - 36; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Long-term visual memory - remote assessment	18 months	Assessed by: Long-term memory subtest of the Rey-Osterrieth Complex Figure: - Range: 0 - 36; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
IEDYERTA - remote assessment	18 months	IED Total Errors (Adjusted): The total number of times that the subject chose a wrong stimulus - i.e. one incompatible with the current rule, adjustment for every stage that was not reached. Lower is better. Total Errors Adjusted = Total Errors (problems reached) + \[(number of unreached problems) \* (25)\] This is a measure of the subject's efficiency in attempting the test. Subjects failing at any stage of the test will have had less opportunity to make errors. The adjustment is carried out to compensate for this missing data, and provide a more comparable error score to subjects completing all stages of the test..; Assessed by: Intra-Extra Dimensional test from CANTAB battery.; - Raw score range: 0 - 402. Lower is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
IEDYCOST - remote assessment	18 months	IED Stages Completed: This is the total number of stages the subject completed successfully. There are nine stages to be completed. Higher is better.; Assessed by: Intra-Extra Dimensional test from CANTAB battery.; - Range: 0 - 9. Higher is better.
SWM Within Errors - remote assessment	18 months	SWM Within Errors: The number of times a subject revisits a box already shown to be empty during the same search. Calculated across all assessed four, six and eight token trials.; Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 0 - 153. Lower is better.
SWMS - remote assessment	18 months	SWM Strategy (6-8 boxes): The number of times a subject begins a new search pattern from the same box they started with previously. If they always begin a search from the same starting point we infer that the subject is employing a planned strategy for finding the tokens. Therefore a low score indicates high strategy use (1 = they always begin the search from the same box), a high score indicates that they are beginning their searches from many different boxes. Calculated across assessed trials with 6 tokens or 8 tokens.; Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 2 - 14. Lower is better.; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased
ERTTHF - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total Hits Fear: The total number of times the subject correctly selected the emotion 'Fear'. Calculated across all assessed trials.; - Range: 0 - 15 . Higher is Better
ERTTHSU - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery; ERT Total Hits Surprise: The total number of times the subject correctly selected the emotion 'Surprise'. Calculated across all assessed trials.; - Range: 0 - 15 . Higher is Better.
ERTTFAS - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total False Alarms Sadness: The total number of times the subject incorrectly selected the emotion 'Sadness'. Calculated across all assessed trials.; - Range: 0 - 75 . Lower is Better.
ERTTFAF - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total False Alarms Fear: The total number of times the subject incorrectly selected the emotion 'Fear'. Calculated across all assessed trials.; - Range: 0 - 75 . Lower is Better.
5DT Inhibition - remote assessment	18 months	Assessed by: Inhibition subtest from 5 digit test: time; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
5DT Flexibility - remote assessment	18 months	Assessed by: Flexibility subtest from 5 digit test: time; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
SWMPR - remote assessment	18 months	SWM Problem Reached: This measure reports the problem number that the subject reached, but did not necessarily complete.; Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 2 - 6. Higher is better.
ERTTHS - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total Hits Sadness: The total number of times the subject correctly selected the emotion 'Sadness'. Calculated across all assessed trials.; - Range: 0 - 15 . Higher is Better
ERTTFASU - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total False Alarms Surprise: The total number of times the subject incorrectly selected the emotion 'Surprise'. Calculated across all assessed trials.; - Range: 0 - 75 . Lower is Better.
ERTUHRSU - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Unbiased Hit Rate Surprise: The unbiased hit rate ensures that recognition accuracy of the Surprise emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Anger trials only.; - Range: 0 to 1. Higher is better.
Semantic fluency - remote assessment	18 months	Assessed by: Semantic fluency test: * Produce names of fruits and vegetables in 1 minute (Test Barcelona - Revised) (for ADULTS); * Number of name of animals recalled in 1 minute + number of name of food and drinks recalled in 1 minute: from 0 to infinity (NEPSY - II) (for CHILDREN); Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Psychiatric symptoms/disorders in remote assessments	18 months	Number of participants with psychiatric symptoms/disorders following DSM-IV-TR guidelines (psychotic symptoms, symptoms of depression, symptoms of mania, global functioning).
EEG reactivations in working memory	18 months	This is quantified by training decoders of memorized locations on EEG signals acquired over several electrodes during the working memory task. Reactivations are the average strength of the decoders during the fixation period of the next trial. We expect that EEG reactivations increase as patients improve clinically and correlate with the serial bias index.
Serial bias in working memory	18 months	This is quantified from the participant responses in the working memory task. Errors in the report of memorized locations are multiplied by the sign of the difference in locations in the previous and current trials and then averaged over the whole session to obtain the index of serial bias. We expect increases in this index as patients improve clinically.
SWMSX - remote assessment	18 months	SWM Strategy (6-12 boxes): The number of times a subject begins a new search pattern from the same box they started with previously. If they always begin a search from the same starting point we infer that the subject is employing a planned strategy for finding the tokens. Therefore a low score indicates high strategy use (1 = they always begin the search from the same box), a high score indicates that they are beginning their searches from many different boxes. Calculated across assessed trials with 6 tokens or more.; Assessed by: Spatial Working Memory test from CANTAB battery: - Range: 3 - 26. Lower is better.
ERTTH - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total Hits: The total number of times the subject selected the correct emotion. Calculated across all assessed trials.; - Range: 0 - 90. Higher is Better
ERTTHA - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total Hits Anger: The total number of times the subject correctly selected the emotion 'Anger'. Calculated across all assessed trials.; - Range: 0 - 15 . Higher is Better
ERTTFAA - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total False Alarms Anger: The total number of times the subject incorrectly selected the emotion 'Anger'. Calculated across all assessed trials.; - Range: 0 - 75 . Lower is Better.
ERTTFAD - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Total False Alarms Disgust: The total number of times the subject incorrectly selected the emotion 'Disgust'. Calculated across all assessed trials.; - Range: 0 - 75 . Lower is Better.
ERTUHRH - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Unbiased Hit Rate Happiness: The unbiased hit rate ensures that recognition accuracy of the Happiness emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Happiness trials only.; - Range: 0 to 1. Higher is better.
ERTUHRS - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Unbiased Hit Rate Sadness: The unbiased hit rate ensures that recognition accuracy of the Sadness emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Sadness trials only; - Range: 0 to 1. Higher is better.
ERTUHRA - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Unbiased Hit Rate Anger: The unbiased hit rate ensures that recognition accuracy of the Anger emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Anger trials only.; - Range: 0 to 1. Higher is better.
ERTUHRSD - remote assessment	18 months	Assessed by: Emotion Recognition Task from CANTAB battery.; ERT Unbiased Hit Rate Disgust: The unbiased hit rate ensures that recognition accuracy of the Disgust emotion is not influenced by response guessing or response bias effects. It takes into consideration the joint probability of an individual making a correct response, based on the presentation of the correct stimulus out of the available possibilities. Calculated for assessed Disgust trials only.; - Range: 0 to 1. Higher is better.
Phonemic fluency - remote assessment	18 months	Assessed by: Phonemic fluenct test: * Produce words that start with letter M in 1 minute: range from 0 to infinity (Test Barcelona - Revised) (for ADULTS); * Number of words started by letter "P" recalled in 1 minute + number of words started by letter "M" in 1 minute: range: from 0 to infinity (NEPSY-II) (for CHILDREN).; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Naming - remote assessment	18 months	Assessed by: Boston Naming Test (BNT): - Range: from 0 to 60; Raw scores were transformed into standard T-scores (mean 50 ± standard deviation \[SD\] 10) and a score below 35 (≤ 1.5 SD below normative mean, or the equivalent ≤9th percentile) was considered significantly decreased.
Naming with cues - remote assessment	18 months	Assessed by: Boston Naming Test (BNT); - Total correct with phonemic cue: from 0 to 60

Trial Locations

Locations (1)

Hospital Clínic de Barcelona; 🇪🇸 Barcelona, Cataluña, Spain