Apathy and impulsivity in frontotemporal lobar degeneration syndromes

Lansdall et al. reveal the structural brain changes leading to different types of apathy and impulsivity, across the spectrum of disorders caused by frontotemporal lobar degeneration, including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. The positive correlation between apathy and impulsivity indicates the need for a unified therapeutic strategy.

Demographics and disease characteristics by diagnostic group, split into equally weighted groups of PSP, CBS, bvFTD and PPA. Note that PPA included 12 nvPPA, 11 svPPA and 11 "PPA other" cases (2 lvPPA and the remaining not meeting criteria for either svPPA or nvPPA and therefore unspecified).

A Detailed Description of Behavioural Tasks
Motor and Saccadic Go/NoGO Task The Go/NoGO task is a measure of response inhibition, specifically action restraint, which is distinct from action cancellation measured by the stop signal task. The saccade Go/NoGO task is explained in detail in the main text. The motor NoGO task was analogous to the saccadic task but used a joystick operated by the dominant hand (except where physical disability impaired hand use, in which case the most physically able hand was used). Stimuli were presented on a laptop screen positioned 1m from the subject, with the initial red and green cues The CRRT is an assessment of incentive motivation, designed to assess responsiveness to reward signals on an odd one out task (Cools et al., 2005). The task was simplified from the original CRRT to 2 colour/probability options instead of 3 and 50 trials instead of 100. The task was run on a laptop with responses recorded by a 3-button box (dominant hand). Forty practice trials without feedback were used to familiarize the participant with the task and to titrate reaction time thresholds for each individual (to ensure motivationally relevant signals were tailored to individual differences in cognitive speed) using a cut-off value for reward feedback of mean reaction time minus one standard deviation. Participants were presented with a cue (coloured rectangle), signaling the probability of reward following a correct response, either 20% or 80%. Participants were informed that the chance of receiving feedback was dependent on the colour of the box surrounding the presented circles, but were not informed which colour was more likely to give feedback. Participants then identified the 'odd-one-out' of three presented circles. Feedback was; 100 points for a correct and fast response, 1 point for a correct but slow response and 0 points for an incorrect response. Participants were instructed to obtain as many points as possible, for which normal controls demonstrate a "reinforcementrelated speeding" effect: responding quicker under the anticipation of increased probability of reward (Cools et al., 2005;G. K. Murray et al., 2008). In order to assess the impact of learning, we examined the mean RT at both reward probability values for the first half (FH) and second half (SH) of trials and then calculated the reward-related speeding effect (eg. First half mean RT 20% probability -First half mean RT 80% probability). We subsequently calculated the overall reinforcement related speeding (Speeding SH -Speeding FH). We further examined the impact of feedback on speed of response to the subsequent trial, providing a measure of response to positive and negative stimuli (positive feedback mean RT and negative feedback mean RT calculated). Additional outcome variables included total errors and total score.

Information Sampling Task (IST)
The Cambridge Neurospychological Test Automated Battery (CANTAB) IST (Clark et al., 2006) was administered on a touch screen computer to assess reflection impulsivity using five fixed condition and five descending win condition trials. Participants were presented with a 5x5 matrix of 25 grey boxes which, when selected, turned blue/yellow. On fixed trials, participants were instructed to open as many boxes as they liked, before deciding whether there were mostly blue or yellow boxes. On decreasing trials, every selected box subtracted 10 points from a starting sum of 250, to encourage faster decision making based on limited information.
Correct responses were rewarded with 100 points and incorrect were punished -100 points.
Outcome measures were determined for fixed and decreasing win trials (Cambridge Cognition Ltd.) and included the probability of being correct at the time of making the decision (pCorrect), mean box opening latency (boxLatency, mean colour decision latency (colourLatency), mean boxes opened per trial (boxesOpened), incorrect decisions based on insufficient evidence (sampling error), incorrect decision based on available evidence (discrimination errors) and total correct decisions (tCorrect).

Stop Signal Task (SST)
The SST is a response inhibition (impulse control) task focusing specifically on action cancellation (Chamberlain et al., 2007). The SST was administered using the CANTAB and a two button press pad. In the first practice part (16 trials), stimuli were presented on a computer screen and participants were instructed to press the right/left button as quickly as possible in response to the right/left arrow. The second part consisted of 64 trials, by which participants were instructed to continue responding as quickly as possible, but to refrain from responding when they heard an auditory signal (beep), presented in 25% of trials (randomly dispersed).
The delay between presentation of the arrow stimuli and the stop signal varied, known as the stop signal delay), in order to give an estimate of the stop signal reaction time (SSRT; the time it takes to successfully inhibit a response). The SSRT, the primary outcome measure, is calculated by subtracting the mean SSD at which a participant is able to inhibit responding on 50% of trials (SSD 50) from the mean reaction time on go trials (no stop signal). Following successful inhibition, SSD decreased and when participants failed to inhibit responding, SSD increased. The major outcome variables included SSD, SSRT, total correct responses on stop and go trials, direction errors on stop and go trials, mean/median reaction times for all go trials.

Cambridge Gambling Task (CGT)
The CGT is a unique task assessing decision-making and risk taking behavior in the absence of learning or information retrieval. It dissociates risk taking from impulsivity, as participants have to wait for a risky bet in the ascending condition (Manes et al., 2002). The task was administered using the CANTAB and consisted of a neutral part and two gambling parts.
Participants were presented with a row of red and blue boxes at the top of the screen, and were instructed to guess which colour box a yellow token was placed under. Participants responded by touching the boxes containing the words 'Red' or 'Blue' at the bottom of the screen.
In the gambling stages, participants started with 250 points and could select how confident they are with their decision by gabling a certain proportion of these points, which were displayed on the right hand side of the screen in either ascending (part 1) or descending (part 2) order.
Participants were instructed to obtain as many points as possible, and the total accumulated points is displayed on the screen throughout.
Note: The CGT was removed from the protocol after 37 participants due to floor effects and difficult task engagement by FTLD patients, even following simplification of the task. This highlights the need to develop a disease-specific task to look at gambling behaviours in FTLD syndromes.
Below are the multi-slice figures for all principal components with significant grey and white matter correlates (threshold p<.005, FWEc p<.05). These include white matter correlates for Components 1-3 and 7 and grey matter correlates for Components 2-4 and 7.