Stimulation of STN impairs aspects of cognitive control in PD

Spatial delayed response task.

The spatial delayed response (SDR) task17 is an experimentally derived working memory task that has been closely linked to lateral prefrontal cortex functioning in animals and humans.18-22⇓⇓⇓⇓ Working memory tasks require individuals to maintain, monitor, and use internal information to guide behavior and thus engage cognitive control processes. Working memory load was varied to require different levels of these control processes. Working memory is thought to be a fundamental cognitive skill that supports many other more complex “executive” functions such as planning and organizing complex behavior, reading comprehension, fluid intelligence, and the capacity to draw inferences.23,24⇓ PD patients are impaired on verbal and spatial working memory tasks, even at the beginning stages of their disease25-27⇓⇓ (perhaps because of altered caudate-modulated basal ganglia output or changes in mesocortical dopaminergic pathways).28 Poor working memory performance correlates with increased severity of PD26 and with worse Mini-Mental State Examination (MMSE) scores.27 Cognitive impairment as measured by the MMSE in PD is strongly related to decreased quality of life.29

In this task, subjects focused on a central fixation cross on a computer screen placed approximately 60 cm away from the subject. While fixated, either one or two cues (each 1 cm in diameter) appeared for 150 milliseconds in any of 32 possible unmarked locations at an 11.5-cm radius from the central fixation. A delay period (5 or 15 seconds) was then imposed. During the delay, subjects performed a continuous performance task in which a series of geometric shapes (triangle, square, and diamond) appeared in place of the fixation cross (1,000-millisecond duration, 750- to 1,250-millisecond intertrial interval). Subjects pressed the spacebar whenever the diamond shape appeared. Reaction times and accuracy rates were recorded. After the delay, the fixation cue returned, and subjects pointed on the computer screen where they remembered seeing the cue(s). Responses were measured in X and Y coordinates and compared with the actual location of the cue. Delay trials and trials with no mnemonic load (cue-present trials) were presented in random order. On the cue-present trials, the cue was present during the response phase. This set of trials gave an indication of subjects’ pointing accuracy. Mean error in millimeters (distance between recall and actual target) was calculated for each subject for each type of trial. There were either one or two cues to be remembered on each trial. In the two-cue condition, both locations were presented simultaneously, and in the recall phase, subjects pointed to both locations, in any order desired. Forty experimental trials were presented: 20 with only one cue presented and 20 with two cues presented. Trials were blocked by number of cues. Within each block, conditions (cue present, 5-second delay, 15-second delay) were presented in random order. The order of blocks was counterbalanced across subjects. Subjects performed four cue-present trials and eight trials per delay for each block.

Go–No–Go task.

The Go–No–Go (GNG) task assessed the ability to inhibit a prepotent response under conditions of low or high prepotent response strength30-32⇓⇓ and requires active cognitive control processes such as conflict monitoring. Response inhibition skills are thought to play a role in the effortful control of behavior and the guidance of behavior by internal rather than external cues. These skills are necessary for optimal performance on a variety of complex tasks including working memory, set shifting, and/or maintenance.30-33⇓⇓⇓ PD patients are impaired on tasks emphasizing response inhibition,33 perhaps owing to altered basal ganglia output to anterior cingulate cortex or altered mesocortical dopaminergic pathways. Poor performance significantly predicts later cognitive decline and correlates with overall UPDRS scores.33,34⇓

This task involved monitoring a visual display while single uppercase letters were presented one at a time interspersed with the number 5 (250-millisecond duration, 1,000-millisecond intertrial interval). In this task, participants were instructed to push a target response button at the occurrence of every letter but to withhold a response when the number 5 was presented. Target frequency (percentage of trials where a button press was required, e.g., letters) was manipulated in a blocked fashion. There were two levels of target frequency (medium = 50%; high = 83%). The high target frequency block is designed to produce a strong prepotent response (e.g., press the button) and so is more challenging for response inhibition skills. One block at each frequency level was performed with the order randomly determined for each subject. Each block contained 150 trials. Reaction times and accuracy rates were recorded.

SDR test.

There was an interaction between memory load and stimulator condition (F[1,22] = 11.3, p = 0.003). Performance became less accurate (paired t-test, t = −2.2, p = 0.04) with stimulation in the two-cue condition but did not change in the one-cue condition (paired t-test, t = 0.22, p = 0.82) (figure 1A). In addition, the main effect of memory load was significant (two-cue performance worse than one-cue overall, F[1,22] = 35.4, p < 0.001; in the off condition, p = 0.001, and in the on condition, p < 0.001, paired t-tests), but main effect of stimulator condition was not (F[1,22] = 0.76, p = 0.39). The difference between subjects who were tested off first and subjects who were tested on first on change in the two-cue, 15-second delay condition was not significant (t-test, t = −0.90, p = 0.38).

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Figure 1. Effects of subthalamic nucleus (STN) stimulation on cognitive control. (A) Mean ± SEM spatial delayed response (SDR) performance (0 = perfect recall) on the 15-second delay, one-cue, and two-cue trials with bilateral stimulators off and on. Turning stimulators on decreased accuracy on the two-cue condition (increased recall error). (B) Mean ± SEM Go–No–Go (GNG) discriminability (1 = perfect performance) on medium and high target frequency conditions with bilateral stimulators off and on. Turning stimulators on decreased discriminability on the high target condition only (decreased accuracy).

The interaction between memory load, stimulator condition, and delay length was significant when all delay conditions (cue present, 5 and 15 seconds) were considered (F[2,21] = 5.3, p = 0.01). When the cue-present and 5-second delay conditions were considered separately, the main effects of stimulator condition and memory load and the interaction between the two variables were not significant (cue present: interaction, F[1,22] = 0.63, p = 0.44; main effect of condition, F[1,22] = 0.01, p = 0.93; main effect of memory load, F[1,22] = 1.87, p = 0.19); 5 seconds: interaction, F[1,22] = 0.5, p = 0.82; main effect of condition, F[1,22] = 3.2, p = 0.09; main effect of memory load, F[1,22] = 2.25, p = 0.15). In addition, there was no effect of stimulator condition or memory load on the delay period task performance in terms of correct hits or median reaction times (F[1,19] < 1.00, p > 0.33).

GNG test.

The interaction between target frequency and condition on GNG discriminability was not significant (F[1,20] = 3.6, p = 0.07), nor was the main effect of condition (F[1,20] = 2.82, p = 0.11). The main effect of target frequency was significant (high target frequency performance worse than medium target frequency overall, F[1,20] = 30.9, p < 0.001; in the off condition, p = 0.02, and in the on condition, p < 0.001, paired t-tests). To test the primary hypothesis further, each target frequency level was considered separately. Stimulator condition did have an effect on GNG discriminability for the high target frequency condition (paired t-test, t = 2.06, p = 0.05) but not for the less demanding medium target frequency GNG condition (paired t-test, t = −0.56, p = 0.58) (see figure 1B).

The main effect of stimulator condition and the interaction between stimulator condition and target frequency on median reaction times (correct hits only) were not significant (stimulator condition: F[1,21] = 1.78, p = 0.20; target frequency: F[1,21] = 0.63, p = 0.44; table 2). There was a main effect of target frequency on reaction time, with faster reaction times in the high target frequency condition (F[1,21] = 32.71, p < 0.001). In post hoc paired t-tests, this effect was significant in both the off (t = −3.6, p = 0.002) and the on (t = −4.6, p < 0.001) stimulator conditions.

As an exploratory analysis, correlations were performed between individual change in reaction times and accuracy on the GNG task across stimulator conditions. Stimulator-related reductions in GNG discriminability correlated with reductions in reaction time in the high but not medium target frequency level (high: r = 0.50, p = 0.02; medium: r = −12, p = 0.62) (figure 2). Decreases in GNG discriminability appeared to reflect primarily decreased nontarget accuracy (increased false alarms), as change in discriminability correlated with change in nontarget accuracy (r = 0.94, p < 0.001) but not change in target accuracy (r = −0.08, p = 0.73).

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Figure 2. Relationship between reaction time and discriminability on the Go–No–Go (GNG) task across stimulator conditions. Percentage change in GNG discriminability across stimulator conditions correlated significantly with percentage change in reaction time across stimulator conditions.

There were no differences in high target performance variables between subjects who were tested off first and subjects who were tested on first (t-tests, p > 0.08). The correlation between change in GNG high target discriminability and change in the SDR 15-second two-cue condition was not significant (r = 0.28, p = 0.23). Correlations between change in UPDRS Motor rating and change in GNG high target discriminability or the SDR 15-second two-cue condition were not significant (GNG: r = −0.20, p = 0.38; SDR: r = 0.04, p = 0.84).