Darlene Floden

Epigenetics of personality traits: An illustrative study of identical twins discordant for risk-taking behavior

DNA methylation differences between identical twins could account for phenotypic twin discordance of behavioral traits and diseases. High throughput epigenomic microarray profiling can be a strategy of choice for identification of epigenetic differences in phenotypically different monozygotic (MZ) twins. Epigenomic profiling of a pair of MZ twins with quantified measures of psychometric discordance identified several DNA methylation differences, some of which may have developmental and behavioral implications and are consistent with the contrasting psychometric profiles of the twins. In particular, differential methylation of CpG islands proximal to the homeobox DLX1 gene could modulate stress responses and risk taking behavior, and deserve further attention as a potential marker of aversion to danger. The epigenetic difference detected at DLX1 of approximately 1.2 fold change was used to evaluate experimental design issues such as the required numbers of technical replicates. It also enabled us to estimate the power this technique would have to detect a functionally relevant epigenetic difference given a range of 1 to 50 twin pairs. We found that use of epigenomic microarray profiling in a relatively small number (15-25) of phenotypically discordant twin pairs has sufficient power to detect 1.2 fold epigenetic changes.

Impact of mild cognitive impairment on outcome following deep brain stimulation surgery for Parkinson's disease.

INTRODUCTION Unlike dementia, the effect of mild cognitive impairment (MCI) on outcomes after deep brain stimulation (DBS) in Parkinsons disease (PD) is less clear. We aimed to examine the effect of MCI on short- and long-term DBS outcomes. METHODS To study the effect of MCI type, cognitive domains (attention, language, visuospatial, memory, executive function), and Dementia Rating Scale (DRS) score on immediate postoperative outcomes (postoperative confusion, hospitalization days), PD patients who underwent DBS at our Center from 2006 to 2011 were analyzed. To determine cognitive predictors of intermediate (6-month) and long-term (1-year) post-operative outcomes, the changes in functional and quality-of-life (QOL) scores were analyzed in a smaller group with available preoperative health status measures. RESULTS We identified 130 patients [71% male, mean age: 63 ± 9.1, mean PD duration: 10.7 ± 5.1]. At preoperative assessment, 60% of patients had multiple-domain MCI, 21% had single-domain MCI, and 19% had normal cognition. MCI presence and type as well as DRS performance did not affect immediate outcomes. Attention impairment predicted longer postoperative hospitalization (P = 0.0015) and showed a trend towards occurrence of postoperative confusion (P = 0.089). For intermediate and long-term outcomes we identified 56 patients [73.2% male, mean age: 61.3 ± 9.6, mean PD duration: 10.6 ± 4.7]. Visuospatial impairment showed a trend towards less improvement in 6-month functional score (P = 0.0652), and 1-year QOL score (P = 0.0517). CONCLUSION The presence of MCI did not affect DBS outcomes. However, the types of impaired domains were more detrimental. Detailed cognitive testing can help stratify low- and high-risk patients based on their pattern of cognitive dysfunction.

Comprehensive, Multidisciplinary Deep Brain Stimulation Screening for Parkinson Patients: No Room for “Short Cuts”

Careful, often cumbersome, screening is a fundamental part of DBS evaluation in Parkinsons disease (PD). It often involves a brain MRI, neuropsychological testing, neurological, surgical, and psychiatric evaluation, and “ON/OFF” motor testing. Given that DBS has now been a standard treatment for advanced PD, with clinicians’ improved comfort and confidence in screening and referring patients for DBS, we wondered whether we can now streamline our lengthy evaluation process. We reviewed all PD patients evaluated for DBS at our center between 2006 and 2011 and analyzed the reasons for exclusion and for dropping out despite passing the screening process. A total of 223 PD patients who underwent DBS evaluation had complete charting. Only 131 (58.7%) patients were successfully implanted. Sixty‐one (27.3%) patients were excluded after screening because of significant cognitive decline (32.7%), early disease with room for medication adjustment (29.5%), behavioral dysfunction (21.3%), suspected secondary parkinsonism or atypical parkinsonism syndrome (13.1%), PD, but with poor levodopa response (11.4%), unrealistic goals (9.8%), PD with predominant axial symptoms (6.5%), significant comorbidities (6.5%), or abnormal brain imaging (3.2%). In addition, 31 (13.9%) patients were cleared for surgery, but either chose not have it (18 patients), were lost to follow‐up (12 patients), or were denied by medical insurance (1 patient). Through careful screening, a significant percentage of surgical candidates continue to be identified as less suitable because of a variety of reasons. This underscores the continued need for a comprehensive, multidisciplinary screening process.

Estimating risk of word-finding problems in adults undergoing epilepsy surgery

Objective: This retrospective, observational study examined the frequency and magnitude of change in naming ability as a function of side/site of epilepsy surgery and identified predictive factors to assist clinicians in identifying patients at low, moderate, or high risk of postoperative naming decline. Methods: A total of 875 adults with pharmacoresistant epilepsy (454 left/421 right; 763 temporal/87 frontal/25 posterior quadrant) met inclusion criteria and completed the Boston Naming Test before and after surgery. Clinically meaningful change in naming ability was assessed using reliable change indices for epilepsy. Demographic, cognitive, and seizure variables were examined to determine factors most predictive of naming decline and to develop a decision tree to assist with clinical decision-making. Results: Naming decline was rare in right-sided resections and did not exceed the level expected by chance (5% overall; 90% confidence interval [CI] ± 2%). Naming decline occurred in 41% (CI ± 5%) of patients after left temporal resection (TLR) compared to 10%–12% (CI ± 10%–19%) in other left-sided surgical groups. A sizable proportion of left TLR patients (17%; CI ± 4%) showed substantial declines in naming (>11 points). Decline following left TLR was related to later age at seizure onset, older age at surgery, and higher preoperative naming ability. These factors correctly predicted naming decline in 68% of patients and were associated with degree of decline following left TLR. A decision tree is provided to assist clinicians in identifying patients at low, moderate, or high risk for postoperative naming declines. Conclusions: In addition to discussions regarding risk for memory decline following left TLR, patients should be counseled about potential decline in word-finding ability.

Similarities in the patterns of prefrontal cortex activity during spatial and temporal context memory retrieval after equating for task structure and performance.

Event-related functional magnetic resonance imaging was used to assess healthy adults while they performed spatial and temporal context memory tasks matched in task structure. After equating task structure between spatial versus temporal context tasks, subjects reported using similar strategies across tasks and we observed no significant differences in accuracy and reaction time performance between tasks. We used three methods of statistical analysis to interrogate similarities and differences in whole-brain activity across retrieval tasks, while focussing on prefrontal cortex (PFC) activations: multivariate partial least squares analysis (PLS), univariate statistical parametric mapping (SPM) and conjunction analysis. The PLS and conjunction analyses indicated that the overall pattern of PFC activity was similar across both temporal and spatial context retrieval tasks; but the SPM results indicated that some of these PFC regions exhibited differences in the degree to which they were engaged between tasks. However, none of these methods identified unique PFC activations specific to mediating spatial and/or temporal context retrieval. These results indicate that, overall, similar patterns of PFC activity were observed during temporal and spatial context memory retrieval once task structure and performance were equated.

Global cognitive scores do not predict outcome after subthalamic nucleus deep brain stimulation

Presence of dementia is a contraindication for DBS treatment of Parkinsons disease. Recent evidence suggests that borderline cognitive function, as measured with a common screening measure, the Mattis Dementia Rating Scale, has a negative impact on quality of life (QoL) after DBS of the STN.

Early event related fields during visually evoked pain anticipation.

OBJECTIVE Pain experience is not only a function of somatosensory inputs. Rather, it is strongly influenced by cognitive and affective pathways. Pain anticipatory phenomena, an important limitation to rehabilitative efforts in the chronic state, are processed by associative and limbic networks, along with primary sensory cortices. Characterization of neurophysiological correlates of pain anticipation, particularly during very early stages of neural processing is critical for development of therapeutic interventions. METHODS Here, we utilized magnetoencephalography to study early event-related fields (ERFs) in healthy subjects exposed to a 3 s visual countdown task that preceded a painful stimulus, a non-painful stimulus or no stimulus. RESULTS We found that the first countdown cue, but not the last cue, evoked critical ERFs signaling anticipation, attention and alertness to the noxious stimuli. Further, we found that P2 and N2 components were significantly different in response to first-cues that signaled incoming painful stimuli when compared to non-painful or no stimuli. CONCLUSIONS The findings indicate that early ERFs are relevant neural substrates of pain anticipatory phenomena and could be potentially serve as biomarkers. SIGNIFICANCE These measures could assist in the development of neurostimulation approaches aimed at curbing the negative effects of pain anticipation during rehabilitation.

A Magnetoencephalography study of multi-modal processing of pain anticipation in primary sensory cortices

Pain anticipation plays a critical role in pain chronification and results in disability due to pain avoidance. It is important to understand how different sensory modalities (auditory, visual or tactile) may influence pain anticipation as different strategies could be applied to mitigate anticipatory phenomena and chronification. In this study, using a countdown paradigm, we evaluated with magnetoencephalography the neural networks associated with pain anticipation elicited by different sensory modalities in normal volunteers. When encountered with well-established cues that signaled pain, visual and somatosensory cortices engaged the pain neuromatrix areas early during the countdown process, whereas the auditory cortex displayed delayed processing. In addition, during pain anticipation, the visual cortex displayed independent processing capabilities after learning the contextual meaning of cues from associative and limbic areas. Interestingly, cross-modal activation was also evident and strong when visual and tactile cues signaled upcoming pain. Dorsolateral prefrontal cortex and mid-cingulate cortex showed significant activity during pain anticipation regardless of modality. Our results show pain anticipation is processed with great time efficiency by a highly specialized and hierarchical network. The highest degree of higher-order processing is modulated by context (pain) rather than content (modality) and rests within the associative limbic regions, corroborating their intrinsic role in chronification.

Effect of apolipoprotein ε4 allele on hippocampal and brain volume in intractable temporal lobe epilepsy.

This study investigated the relationship between the apolipoprotein (APOE) ε4 allele and brain volumes in patients with medically intractable temporal lobe epilepsy (TLE). MRI-based volumetric analyses of the hippocampi, cerebral hemispheres, and whole brain were conducted in 59 patients with TLE (31 with left TLE, 28 with right TLE) with hippocampal sclerosis (HS). There were no differences in hippocampal, hemispheric, or whole brain volumes as a function of ε4 status even after correcting for hemispheric and total brain volumes. However, APOE ε4 carriers showed a trend toward having a smaller discrepancy between ipsilateral and contralateral hippocampal volumes than patients without this allele, and post hoc analyses suggest there may be an increased incidence of bilateral HS in ε4 carriers. In summary, APOE ε4 is not associated with significant hippocampal, hemispheric, or whole brain atrophy in patients with medically intractable TLE. However, ε4 carriers may be more likely to have bilateral HS, with an apparent dose-dependent effect.

Predictors of Functional and Quality of Life Outcomes following Deep Brain Stimulation Surgery in Parkinson’s Disease Patients: Disease, Patient, and Surgical Factors

Objective The primary objective was to evaluate predictors of quality of life (QOL) and functional outcomes following deep brain stimulation (DBS) in Parkinsons disease (PD) patients. The secondary objective was to identify predictors of global improvement. Methods PD patients who underwent DBS at our Center from 2006 to 2011 were evaluated by chart review and email/phone survey. Postoperative UPDRS II and EQ-5D were analyzed using simple linear regression adjusting for preoperative score. For global outcomes, we utilized the Patient Global Impression of Change Scale (PGIS) and the Clinician Global Impression of Change Scale (CGIS). Results There were 130 patients in the dataset. Preoperative and postoperative UPDRS II and EQ-5D were available for 45 patients, PGIS for 67 patients, and CGIS for 116 patients. Patients with falls/postural instability had 6-month functional scores and 1-year QOL scores that were significantly worse than patients without falls/postural instability. For every 1-point increase in preoperative UPDRS III and for every 1-unit increase in body mass index (BMI), the 6-month functional scores significantly worsened. Patients with tremors, without dyskinesia, and without gait-freezing were more likely to have “much” or “very much” improved CGIS. Conclusions Presence of postural instability, high BMI, and worse baseline motor scores were the greatest predictors of poorer functional and QOL outcomes after DBS.