Michele K. York

The Neural Substrates of Reward Processing in Humans: The Modern Role of fMRI

Experimental work in animals has identified numerous neural structures involved in reward processing and reward-dependent learning. Until recently, this work provided the primary basis for speculations about the neural substrates of human reward processing. The widespread use of neuroimaging technology has changed this situation dramatically over the past decade through the use of PET and fMRI. Here, the authors focus on the role played by fMRI studies, where recent work has replicated the animal results in human subjects and has extended the view of putative reward-processing neural structures. In particular, fMRI work has identified a set of reward-related brain structures including the orbitofrontal cortex, amygdala, ventral striatum, and medial prefrontal cortex. Moreover, the human experiments have probed the dependence of human reward responses on learned expectations, context, timing, and the reward dimension. Current experiments aim to assess the function of human reward-processing structures to determine how they allow us to predict, assess, and act in response to rewards. The authors review current accomplishments in the study of human reward processing and focus their discussion on explanations directed particularly at the role played by the ventral striatum. They discuss how these findings may contribute to a better understanding of deficits associated with Parkinson’s disease.

Cognitive declines following bilateral subthalamic nucleus deep brain stimulation for the treatment of Parkinson’s disease

Background: We investigated the cognitive and psychiatric outcome 6 months after bilateral subthalamic nucleus deep brain stimulation (DBS) for the treatment of Parkinson’s disease (PD) using a disease control group. Methods: 23 patients who underwent DBS were compared with 28 medically treated patients with PD at baseline and at 6 months for neuropsychological measures. In addition to the group outcomes, we report reliable change indices (RCI) and a dementia caseness analysis. Results: Patients who underwent DBS demonstrated a significant decline in verbal memory compared with the control group (p<0.003), and trends for decline on oral information processing, including verbal fluency, timed transcription and word naming. Patients who underwent DBS demonstrated declines in attention, set shifting and semantic fluency but these changes were similar to the rate of decline in the PD group. RCI indicated that patients who underwent DBS demonstrated clinically significant declines in verbal fluency (p<0.01) and inhibition of a dominant response (p<0.003), with trends for declines in set shifting (p<0.02) and verbal long term recall (p<0.08), indicative of frontostriatal dysfunction. Patients who underwent DBS did not demonstrate significant changes in depression, anxiety or psychological distress scores. The caseness analysis revealed that one of the patients who underwent DBS (4%) converted to dementia over 6 months compared with none of the PD controls. Conclusions: Our findings demonstrated that patients who underwent DBS experienced declines in verbal recall and trends for declines in oral information processing 6 months following surgery, even when good motor outcome was achieved. Potential candidates should be counselled about the risk of mild frontostriatal cognitive declines following DBS to weigh the risks and benefits of surgery.

Stereotactic pallidotomy for the treatment of Parkinson's disease Efficacy and adverse effects at 6 months in 26 patients

We evaluated the safety and efficacy of microelectrode-guided stereotactic pallidotomy in patients with advanced Parkinsons disease (PD). Using diagnostic criteria and evaluations outlined in the Core Assessment Programme in Transplantation (CAPIT) protocol, we studied unilateral pallidotomy in 26 patients with advanced idiophatic PD, motor fluctuations, and peak dose dyskinesias. All underwent unilateral stereotactic pallidotomy. Assessments conducted in the “practically defined off” and “best on” states at baseline and at 1 and 6 months postoperatively included Unified Parkinsons Disease Rating Scale (UPDRS) parts II, III, and IV and timed motor testing as outlined in CAPIT. Motor UPDRS in the “off” state improved at 1 and 6 months after surgery (p = 0.002, p = 0.008) Likewise, the sum of individual “off” contralateral motor UPDRS items improved (p = 0.0002, p = 0.0005). The duration (p = 0.0001 at 1 and p = 0.001 at 6 months) and severity (p = 0.003 at 1 and p = 0.0005 at 6 months) of dyskinesia improved, but other aspects of the “on” function were unchanged. Serious adverse effects occurred in eight patients and included one fatal deep and three nonfatal frontal lobe hemorrhages with resultant language or behavioral deficits. Nonhemorrhagic complications included one hemiparesis and three frontal lobe syndromes. Pallidotomy improves PD motor disability in the “off” state. Peak dose dyskinesias are reduced, although other aspects of “on” motor function are unchanged. Although morbidity may limit its use, pallidotomy is effective in targeting particular symptoms such as unremitting dyskinesia and severe “off” motor disability in advanced PD.

Detecting frontotemporal dysfunction in ALS: Utility of the ALS Cognitive Behavioral Screen (ALS-CBS™)

Abstract Up to half of patients with ALS develop cognitive impairment during the course of the illness. Despite this, there is no simple tool for screening patients in the clinical setting. This study examines the sensitivity, specificity and accuracy of the ALS Cognitive Behavioral Screen (ALS-CBS™). We administered the measure to 112 ALS patients, including 31 who also underwent comprehensive neuropsychological testing. Screen results were validated by determining the accuracy against the full battery. Optimal cut-off scores for predicting the correct diagnosis were determined, and mean scores were compared between patients, controls and different diagnostic groups. The results demonstrated that mean cognitive scores differed between ALS and normal controls (p <0.0001). The cognitive section differentiated ALS-FTD from other ALS patients with 100% accuracy. Cognitively normal ALS patients could be distinguished from those with any cognitive deficit with 71% specificity and 85% sensitivity. A separate behavioral score was significantly lower in the ALS cohort compared to controls (p <0.0001) and predicted ALS-FTD with 80% sensitivity and 88% specificity. In conclusion, the ALS-CBS™ can aid in detecting cognitive and behavioral impairment in a clinical setting, although it does not replace formal diagnostic assessment. Further validation with larger sample sizes will clarify its clinical utility.

Relationship between neuropsychological outcome and DBS surgical trajectory and electrode location.

BACKGROUND The outcome literature of subthalamic nuclei (STN) deep brain stimulation (DBS) suggests that cognitive declines are commonly reported following surgery. We hypothesized that differences in electrode position and surgical trajectory may lead to a differential neuropsychological outcome. METHODS We conducted a standardized evaluation of the location of the DBS electrode tip and the active electrodes, the surgical trajectory through which they were placed, and their relation to neuropsychological change scores (mental status, verbal memory, verbal fluency, and psychological measures) in 17 bilateral STN DBS patients using 6 months post-surgical magnetic resonance imaging data. RESULTS Declines in mental status scores were related to electrodes that were more posterior-laterally placed within the frontal quadrant in either hemisphere or those located superiorally in the left hemisphere. Electrodes that were closer to the approximated STN and more superiorally located in the left hemisphere were associated with verbal learning declines at 6 months following surgery. In the right hemisphere, the electrodes that were located more in the lateral direction were related to verbal short-term memory declines; while for verbal long-term memory declines were found for electrodes located more posterior-laterally in the left hemisphere. Declines in verbal fluency scores were more variable with associations found between change scores and electrodes in the lateral and superior directions in the left hemisphere and those electrodes closer to the approximated STN and more superiorally and posteriorally located in the right hemisphere. In contrast, semantic fluency declines were only related to right hemisphere electrodes located more superiorally. Declines in mood were related to those electrodes located further away from the approximated STN, particularly those located more inferiorally and laterally in the left hemisphere. Anxiety change scores were not associated with the location of the electrodes. CONCLUSIONS The results provide preliminary evidence that 6 months following bilateral STN DBS cognitive and emotional changes may be related to the surgical trajectory and electrode placement.

A decrease in body mass index is associated with faster progression of motor symptoms and shorter survival in ALS

Abstract Our objective was to test the hypothesis that changes in body mass index (BMI) are associated with changes in the clinical course of ALS. We examined the relationships between BMI at first clinical visit and changes in BMI up to a two-year follow-up, and multiple clinical variables related to ALS: age of onset, rate of progression of motor symptoms, and survival. Baseline BMI was classified according to the World Health Organization (WHO) criteria. Changes in BMI were classified as a loss of >1 unit, no change, or a gain of >1 unit. Our results showed that baseline BMI was not associated with age of onset, rate of progression or survival. In contrast, a loss of BMI >1 over two years was associated with significantly shorter survival and a faster rate of progression. In a multiple regression model, these results were independent of gender, site of onset, history of diabetes mellitus and apolipoprotein (ApoE) genotype. In summary, a change in BMI after ALS diagnosis was significantly associated with rate of progression and survival. This raises the possibility that early changes in BMI may identify patients likely to have a more malignant course of the disease. However, further research is needed to clarify the relationship between BMI and ALS.

ALS disease onset may occur later in patients with pre-morbid diabetes mellitus.

Background  Several metabolic derangements associated with diabetes mellitus type 2 (DM) have been associated with a better outcome in amyotrophic lateral sclerosis (ALS), including hyperlipidemia and obesity. Here, we tested the hypothesis that DM would have a positive effect on the motor and cognitive findings of ALS.

Cognitive Outcome and Reliable Change Indices Two Years Following Bilateral Subthalamic Nucleus Deep Brain Stimulation

Subthalamic nucleus deep brain stimulation (STN-DBS) is currently the treatment of choice for medication-resistant levodopa-related motor complications in patients with Parkinsons disease (PD). While STN-DBS often results in meaningful motor improvements, consensus regarding long-term neuropsychological outcome continues to be debated. We assessed the cognitive outcomes of 19 STN-DBS patients compared to a group of 18 medically-managed PD patients on a comprehensive neuropsychological battery at baseline and two years post-surgery. Patients did not demonstrate changes in global cognitive functioning on screening measures. However, neuropsychological results revealed impairments in nonverbal recall, oral information processing speed, and lexical and semantic fluency in STN-DBS patients compared to PD controls 2 years post-surgery in these preliminary analyses. Additionally, reliable change indices revealed that approximately 50% of STN-DBS patients demonstrated significant declines in nonverbal memory and oral information processing speed compared to 25-30% of PD controls, and 26% of STN-DBS patients declined on lexical fluency compared to 11% of PD patients. Approximately 30% of both groups declined on semantic fluency. The number of STN-DBS patients who converted to dementia 2 years following surgery was not significantly different from the PD participants (32% versus 16%, respectively). Our results suggest that neuropsychological evaluations may identify possible mild cognitive changes following surgery.

Cognitive rehabilitation for executive dysfunction in Parkinson's disease: application and current directions.

Cognitive dysfunction in Parkinsons disease contributes to disability, caregiver strain, and diminished quality of life. Cognitive rehabilitation, a behavioral approach to improve cognitive skills, has potential as a treatment option to improve and maintain cognitive skills and increase quality of life for those with Parkinsons disease-related cognitive dysfunction. Four cognitive rehabilitation programs in individuals with PD are identified from the literature. Characteristics of the programs and outcomes are reviewed and critiqued. Current studies on cognitive rehabilitation in PD demonstrate feasibility and acceptability of a cognitive rehabilitation program for patients with PD, but are limited by their small sample size and data regarding generalization of effects over the long term. Because PD involves progressive heterogeneous physical, neurological, and affective difficulties, future cognitive rehabilitation programs should aim for flexibility and individualization, according to each patients strengths and deficits.

Changes in cognitive-emotional and physiological symptoms of depression following STN-DBS for the treatment of Parkinson’s disease

Background and purpose:  Subthalamic nucleus deep brain stimulation (STN‐DBS) has been shown to have beneficial effects on the motor features of Parkinson’s disease (PD), but its impact on non‐motor symptoms, most notably mood, has not been fully explored.