Inflammation-related Alterations in Neurocircuitry: Reversal With Levodopa

Corticostriatal connectivity was assessed by functional magnetic resonance imaging (fMRI). Resting-state and task-based (monetary incentive delay \[MID\]) fMRI scans were conducted on a 3 Tesla Siemens Trio MRI scanner. Subject-level correlations for degree of cortical and striatal functional connectivity were Fisher's Z transformed {Z(R)=0.5ln\[(1+R)/(1-R)\]}, a standard method for calculating fMRI functional connectivity. Greater Fisher's Z-scores reflected stronger correlated fMRI activity (i.e., higher corticostriatal connectivity).

Time frame: Scans approximately 45 min post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: The number analyzed in one or more rows correspond to the number with available and analyzable resting fMRI scans both pre and post drug and placebo.

Peripheral blood samples were analyzed for levels of immune markers like plasma C-reactive protein (CRP), interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), tumor necrosis factor (TNF) -alpha, soluble cytokine receptor2 (TNFR 2), interleukin-1 beta (IL-1 beta), interleukin-1 receptor antagonist (IL-1Ra), interleukin 10 (IL-10) and monocyte chemoattractant protein-1 (MCP-1).

Time frame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: The number analyzed in each row correspond to the number available and analyzable with resting fMRI scans both pre and post drug and placebo.

The Beck Depression Inventory-II (BDI-II) is a widely used self-report for measuring depression severity over the past two weeks and the anhedonia subscale is one of several validated subscales in the BDI-II. Responses are given on a 4-point scale where 0 = the symptom of depression has not been experienced and 3 = the symptom of depression is severe. The anhedonia subscale score is created by summing responses to four items of the BDI-II that assess loss of pleasure, loss of interest, loss of energy, loss of sex drive. The total score of the anhedonia subscale ranges from 0 to 12 where higher scores reflect greater severity of anhedonia symptoms.

Time frame: Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)

The motivation and pleasure (MAP) questionnaire is an 18-item self-report inventory that was created to disentangle state-wise motivational and consummatory components of everyday activities over a 24-hour period. This scale was used to assess self-reported changes in symptoms of anhedonia before and after inflammation blockade. Respondents respond to statements about daily activities on a scale from 0 (no pleasure/not at all) to 4 (extreme pleasure/very often). Total scores range from 0 to 72 where higher scores indicate greater motivation and effort given to everyday situations.

Time frame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo

Population: This analysis includes participants who completed this assessment.

The Digit Symbol Task was used to assess graphomotor speed, visual scanning and memory processing speed involving numbers and a corresponding blank box where subjects are asked to fill in matching symbol as fast as they can. Results show the average number of correct symbols completed in up to 100 boxes in 90 seconds.

Time frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: This analysis includes participants who completed this assessment and had usable data. One participant in the Placebo/Sinemet arm did not complete this assessment at any time point and one had unusable data for the baseline assessment.

The Effort-Expenditure for Rewards Task (EEfRT) is a computer-based multi-trial task used to objectively assess motivation. Possible results range between 0 to1 with 1 being a better outcome. Results show mean probability of hard (high effort) choice.

Time frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: This analysis includes participants who completed this assessment and had usable data. Two participants in each study arm did not complete this assessment at any time point. Two participants in the Placebo/Sinemet group had unusable data for the baseline assessment.

The Finger Tapping Task (FTT) assesses motor speed and can detect subtle motor impairment. The test measures the average number of taps per 10 second trial. A greater number of taps reflects faster motor speed.

Time frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: This analysis includes participants who completed this assessment and had usable data. One participant in the Placebo/Sinemet arm did not complete this assessment at any time point and one had unusable data for the baseline assessment.

The Inventory of Depressive Symptoms-Self Report (IDS-SR) is a 30-item self-report instrument with excellent psychometric properties for measuring symptom constructs consistent with current Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology and that is widely used to measure depression severity in clinical trials. Response scores are summed and range from 0 to 84, with higher scores reflecting greater depression severity.

Time frame: At baseline and Visit 1: Pre drug/placebo, Visit 2: Pre drug/placebo (spaced by approximately 1 week)

Population: Three participants in the Sinemet/Placebo arm and four participants in the Placebo/Sinemet arm had unusable data for the baseline assessment.

The Multidimensional Fatigue Inventory (MFI) is a 20-item self-report instrument designed to measure severity of fatigue based on five dimensions of fatigue, general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. The total MFI scores range from 20 to 100 where high scores indicate greater fatigue.

Time frame: At baseline and Visit 1, Visit 2 (spaced by approximately 1 week)

The Profile of Mood States (POMS) scale is a 30-item psychological rating scale used to assess transient, distinct mood states. Participants rate the extent to which they feel unhappy, blue, lonely, gloomy, and worthless on a scale from 0 (not at all) to 4 (extremely). Scores range from 0 to 120 with higher scores reflecting a more negative mood state.

Time frame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo

Population: This analysis includes participants who completed this assessment.

The reaction time test includes simple and choice reaction time tasks and is divided into 5 stages requiring increasingly complex chains of responses. The task provided distinction between reaction (or decision) time and movement latencies (milliseconds) based on touch responses made to a single (simple) or chosen from multiple (choice) stimuli flashed on a computer screen. Results show mean response latency in milliseconds.

Time frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: This analysis includes participants who completed this assessment and had usable data. Seven participants in the Sinemet/Placebo arm and 8 participants in the Placebo/Sinemet arm did not complete this assessment at any time point. One participant in each study arm had unusable data for the baseline assessment.

The Snaith-Hamilton Pleasure Scale (SHAPS), a 14-item self-report scale with high psychometric validity for assessing the presence of anhedonia, was used to assess hedonic capacity. Participants rated how much they agreed or disagreed with the 14 items phrased as I would enjoy \_\_ based on their ability to experience pleasure. Of the four possible response categories (Definitely Agree, Agree, Disagree, and Strongly Disagree), either of the Disagree responses received a score of 1 and either of the Agree responses received a score of 0. The SHAPS score calculated as the sum of these 14 items ranged from 0 to 14, and higher SHAPS scores indicated greater anhedonia.

Time frame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo

Population: This analysis includes participants who completed this assessment.

The 20-item self-report State-Trait Anxiety Inventory (STAI) State scale was used to measure severity of anxiety symptoms. Total scores range from 20 to 80 with higher scores reflecting greater anxiety. Scores in the high 40s are considered clinically significant.

Time frame: Visit 1: Pre drug/placebo, Visit 1: 1-2 hrs post drug/placebo, Visit 2: Pre drug/placebo, Visit 2: 1-2 hrs post drug/placebo

Population: This analysis includes participants who completed this assessment.

The Trail Making Test (TMT) is used to measure basic attention and psychomotor processing speed. Time taken to complete each task is recorded in seconds, whereby the greater the number of seconds, the slower the psychomotor speed.

Time frame: At baseline and approximately 2-3 hours post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)

Population: This analysis includes participants who completed this assessment and had usable data. One participant in the Sinemet/Placebo arm and two participants in the Placebo/Sinemet arm did not complete this assessment at any time point. Three participants in the Placebo/Sinemet group had unusable data for the baseline assessment.

The cerebral blood flow (CBF) before and after Sinemet (250 mg levodopa/ 50mg carbidopa) or placebo administration was assessed by arterial spin labeling (ASL) fMRI.

Time frame: Scans approximately 45 minutes post drug/placebo administration at Visit 1, Visit 2 (spaced by approximately 1 week)