Systemic D1-R and D2-R antagonists in non-human primates differentially impact learning and memory while impairing motivation and motor performance.

Dopamine (DA) modulates cognition in part via differential activation of D1 and D2 receptors within the striatum and prefrontal cortex, yet evidence for cognitive impairments stemming from DA blockade or deficiency is inconsistent. Given the predominance of D1 over D2 receptors (R) in the prefrontal cortex of primates, D1-R blockade should more strongly influence frontal executive function (including working memory), while D2-R blockade should impair processes more strongly associated with the dorsal striatum (including cognitive flexibility, and learning). To test how systemic DA blockade disrupts cognition, we administered D1-R and D2-R like antagonists to healthy monkeys while they performed a series of cognitive tasks. Two selective DA receptor antagonist drugs (SCH-23390 hydrochloride: D1/D5-R antagonist; or Eticlopride hydrochloride: D2/D3-R antagonist) or placebo (0.9% saline) were systemically administered. Four tasks were used: (1) 'visually guided reaching', to test response time and accuracy, (2) 'reversal learning', to test association learning and attention, (3) 'self-ordered sequential search' to test spatial working memory, and (4) 'delayed match to sample' to test object working memory. Increased reach response times and decreased motivation to work for liquid reward was observed with both the D1/D5-R and D2/D3-R antagonists at the maximum dosages that still enabled task performance. The D2/D3-R antagonist impaired performance in the reversal learning task, while object and spatial working memory performance was not consistently affected in the tested tasks for either drug. These results are consistent with the theory that systemic D2/D3-R antagonists preferentially influence striatum processes (cognitive flexibility) while systemic D1/D5-R administration is less detrimental to frontal executive function.

Reverse Visually Guided Reaching in Patients with Parkinson's Disease.

In addition to motor symptoms such as difficulty in movement initiation and bradykinesia, patients with Parkinson's disease (PD) display nonmotor executive cognitive dysfunction with deficits in inhibitory control. Preoperative psychological assessments are used to screen for impulsivity that may be worsened by deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, it is unclear whether anti-Parkinson's therapy, such as dopamine replacement therapy (DRT) or DBS, which has beneficial effects on motor function, adversely affects inhibitory control or its domains. The detrimental effects of STN-DBS are more apparent when tasks test the inhibition of habitual prepotent responses or involve complex cognitive loads. Our goal was to use a reverse visually guided reaching (RVGR) task, a hand-based version of the antisaccade task, to simultaneously measure motor performance and response inhibition in subjects with PD. We recruited 55 healthy control subjects, 26 PD subjects receiving treatment with DRTs, and 7 PD subjects receiving treatment with STN-DBS and DRTs. In the RVGR task, a cursor moved opposite to the subject's hand movement. This was compared to visually guided reaching (VGR) where the cursor moved in the same direction as the subject's hand movement. Reaction time, mean speed, and direction errors (in RVGR) were assessed. Reaction times were longer, and mean speeds were slower during RVGR compared to VGR in all three groups but worse in untreated subjects with PD. Treatment with DRTs, DBS, or DBS + DRT improved the reaction time and speed on the RVGR task to a greater extent than VGR. Additionally, DBS or DBS + DRT demonstrated an increase in direction errors, which was correlated with decreased reaction time. These results show that the RVGR task quantifies the benefit of STN-DBS on bradykinesia and the concomitant reduction of proactive inhibitory control. The RVGR task has the potential to be used to rapidly screen for preoperative deficits in inhibitory control and to titrate STN-DBS, to maximize the therapeutic benefits on movement, and minimize impaired inhibitory control.

Integrated robotics platform with haptic control differentiates subjects with Parkinson's disease from controls and quantifies the motor effects of levodopa.

BACKGROUND: The use of integrated robotic technology to quantify the spectrum of motor symptoms of Parkinson's Disease (PD) has the potential to facilitate objective assessment that is independent of clinical ratings. The purpose of this study is to use the KINARM exoskeleton robot to (1) differentiate subjects with PD from controls and (2) quantify the motor effects of dopamine replacement therapies (DRTs). METHODS: Twenty-six subjects (Hoehn and Yahr mean 2.2; disease duration 0.5 to 15 years) were evaluated OFF (after > 12 h of their last dose) and ON their DRTs with the Unified Parkinson's Disease Rating Scale (UPDRS) and the KINARM exoskeleton robot. Bilateral upper extremity bradykinesia, rigidity, and postural stability were quantified using a repetitive movement task to hit moving targets, a passive stretch task, and a torque unloading task, respectively. Performance was compared against healthy age-matched controls. RESULTS: Mean hand speed was 41% slower and 25% fewer targets were hit in subjects with PD OFF medication than in controls. Receiver operating characteristic (ROC) area for hand speed was 0.94. The torque required to stop elbow movement during the passive stretch task was 34% lower in PD subjects versus controls and resulted in an ROC area of 0.91. The torque unloading task showed a maximum displacement that was 29% shorter than controls and had an ROC area of 0.71. Laterality indices for speed and end total torque were correlated to the most affected side. Hand speed laterality index had an ROC area of 0.80 against healthy controls. DRT administration resulted in a significant reduction in a cumulative score of parameter Z-scores (a measure of global performance compared to healthy controls) in subjects with clinically effective levodopa doses. The cumulative score was also correlated to UPDRS scores for the effect of DRT. CONCLUSIONS: Robotic assessment is able to objectively quantify parkinsonian symptoms of bradykinesia, rigidity and postural stability similar to the UPDRS. This integrated testing platform has the potential to aid clinicians in the management of PD and help assess the effects of novel therapies.

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder.

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD17) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.