Auditory oddball responses in the human subthalamic nucleus and substantia nigra pars reticulata.

The auditory oddball is a mainstay in research on attention, novelty, and sensory prediction. How this task engages subcortical structures like the subthalamic nucleus and substantia nigra pars reticulata is unclear. We administered an auditory OB task while recording single unit activity (35 units) and local field potentials (57 recordings) from the subthalamic nucleus and substantia nigra pars reticulata of 30 patients with Parkinson's disease undergoing deep brain stimulation surgery. We found tone modulated and oddball modulated units in both regions. Population activity differentiated oddball from standard trials from 200 ms to 1000 ms after the tone in both regions. In the substantia nigra, beta band activity in the local field potential was decreased following oddball tones. The oddball related activity we observe may underlie attention, sensory prediction, or surprise-induced motor suppression.

Multiculturalism and reported cognitive change in Parkinson's disease.

OBJECTIVE: Subjective cognitive decline (SCD) and how much cognitive decline impacts one's ability to perform instrumental activities of daily living (iADLs) are necessary elements of neuropsychological assessment when diagnosing mild cognitive impairment (MCI) and dementia. Though limited, the literature suggests that culture and self-appraisal of cognitive abilities are related. However, it is unclear if differences exist in the subjective elements of neuropsychological assessments between patients born in Anglosphere countries (Canada, the USA, and the UK) versus immigrants born elsewhere (International Group). METHOD: We conducted a retrospective chart review of advanced Parkinson's disease (PD) patients (n = 764). Reports of SCD and iADL difficulties were extracted from neuropsychological reports and coded by two independent raters. We also examined responses on self- and family-rated questionnaires of executive functioning and iADL difficulties. RESULTS: Anglosphere and International patients did not differ on overall, memory, or attention SCD, or overall iADL difficulties based on interviews. Anglosphere patients reported more executive and language SCD during the interview but International care-partners reported more current executive dysfunction on a questionnaire. International patients and care-partners reported more iADL difficulties on a questionnaire, which they ascribed to motor (not cognitive) symptoms. The effects on questionnaires were small and persisted after accounting for depression severity ratings. CONCLUSION: There were no consistent group differences in the number or pervasiveness of SCD or iADL difficulties reported by Anglosphere versus International groups. Immigration status has limited effect on these subjective elements and they should be given significant weight when diagnosing cognitive dysfunction in PD.

Longitudinal assessment of social cognition in de novo Parkinson's disease patients and its relationship with dopaminergic innervation.

BACKGROUND: Social Cognition (SC) has been scarcely studied in Parkinson's disease (PD), and findings in early disease are controversial. SC encompasses different capacities such as facial emotion recognition (FER); Theory of Mind (ToM), the ability to understand other people's intentions (cognitive-ToM) and emotions (affective-ToM); and self-monitoring, the ability to regulate one's own behavior in social contexts. A relationship between dopaminergic deficit and SC in PD has been suggested. OBJECTIVES: To prospectively assess, over a two-year period, SC in newly diagnosed drug-naïve, cognitively normal and non-depressed PD patients. Furthermore, we aimed to evaluate the relationship between SC and Fluorodopa (Positron Emission Tomography) Ki uptake, which is a marker of dopaminergic depletion. METHODS: We compared SC performance between 25 de novo PD patients and 20 healthy controls (HC), and within-patients at baseline and two-year follow-up. The SC assessment included FER, ToM, as well as self-monitoring measures. The relationship between SC and dopaminergic innervation was also assessed in patients. RESULTS: SC scores did not differ between PD and HC groups at baseline, nor between baseline and follow-up evaluation in PD. A significant positive correlation between self-monitoring and Fluorodopa Ki uptake in the left pallidum in PD patients was found at baseline. At follow-up, ToM (stories) positively correlated with Fluorodopa Ki uptake in the right thalamus and the left putamen. CONCLUSION: SC appears to be preserved in de novo PD and remains stable in the short-term. Although more evidence is needed, our results support a relationship between dopamine innervation in subcortical regions and SC.

Use and detection of a vitamin B1 degradation product yields new views of the marine B1 cycle and plankton metabolite exchange.

Vitamin B1 (thiamin) is a vital nutrient for most cells in nature, including marine plankton. Early and recent experiments show that B1 degradation products instead of B1 can support the growth of marine bacterioplankton and phytoplankton. However, the use and occurrence of some degradation products remains uninvestigated, namely N-formyl-4-amino-5-aminomethyl-2-methylpyrimidine (FAMP), which has been a focus of plant oxidative stress research. We investigated the relevance of FAMP in the ocean. Experiments and global ocean meta-omic data indicate that eukaryotic phytoplankton, including picoeukaryotes and harmful algal bloom species, use FAMP while bacterioplankton appear more likely to use deformylated FAMP, 4-amino-5-aminomethyl-2-methylpyrimidine. Measurements of FAMP in seawater and biomass revealed that it occurs at picomolar concentrations in the surface ocean, heterotrophic bacterial cultures produce FAMP in the dark-indicating non-photodegradation of B1 by cells, and B1-requiring (auxotrophic) picoeukaryotic phytoplankton produce intracellular FAMP. Our results require an expansion of thinking about vitamin degradation in the sea, but also the marine B1 cycle where it is now crucial to consider a new B1-related compound pool (FAMP), as well as generation (dark degradation-likely via oxidation), turnover (plankton uptake), and exchange of the compound within the networks of plankton. IMPORTANCE Results of this collaborative study newly show that a vitamin B1 degradation product, N-formyl-4-amino-5-aminomethyl-2-methylpyrimidine (FAMP), can be used by diverse marine microbes (bacteria and phytoplankton) to meet their vitamin B1 demands instead of B1 and that FAMP occurs in the surface ocean. FAMP has not yet been accounted for in the ocean and its use likely enables cells to avoid B1 growth deficiency. Additionally, we show FAMP is formed in and out of cells without solar irradiance-a commonly considered route of vitamin degradation in the sea and nature. Altogether, the results expand thinking about oceanic vitamin degradation, but also the marine B1 cycle where it is now crucial to consider a new B1-related compound pool (FAMP), as well as its generation (dark degradation-likely via oxidation), turnover (plankton uptake), and exchange within networks of plankton.

Racial and Ethnic Differences in Health-Related Quality of Life for Individuals With Parkinson Disease Across Centers of Excellence.

BACKGROUND AND OBJECTIVES: Racial and ethnic minorities have been underrepresented in Parkinson disease (PD) research, limiting our understanding of treatments and outcomes across all non-White groups. The goal of this research is to investigate variability in health-related quality of life (HRQoL) and other outcomes in patients with PD across different races and ethnicities. METHODS: This was a retrospective, cross-sectional and longitudinal, cohort study of individuals evaluated at PD Centers of Excellence. A multivariable regression analysis adjusted for sex, age, disease duration, Hoehn and Yahr (H&Y) stage, comorbidities, and cognitive score was used to investigate differences between racial and ethnic groups. A multivariable regression with skewed-t errors was performed to assess the individual contribution of each variable to the association of 39-item PD Questionnaire (PDQ-39) with race and ethnicity. RESULTS: A total of 8,514 participants had at least 1 recorded visit. Most of them (90.2%) self-identified as White (n = 7,687), followed by 5.81% Hispanic (n = 495), 2% Asians (n = 170), and 1.9% African American (n = 162). After adjustment, total PDQ-39 scores were significantly higher (worse) in African Americans (28.56), Hispanics (26.62), and Asians (25.43) when compared with those in White patients (22.73, p < 0.001). This difference was also significant in most PDQ-39 subscales. In the longitudinal analysis, the inclusion of cognitive scores significantly decreased the strength of association of the PDQ-39 and race/ethnicity for minority groups. A mediation analysis demonstrated that cognition partially mediated the association between race/ethnicity and PDQ-39 scores (proportion mediated 0.251, p < 0.001). DISCUSSION: There were differences in PD outcomes across racial and ethnic groups, even after adjustment for sex, disease duration, HY stage, age, and some comorbid conditions. Most notably, there was worse HRQoL among non-White patients when compared with White patients, which was partially explained by cognitive scores. The underlying reason for these differences needs to be a focus of future research.

Characterization of memory profile in idiopathic REM sleep behavior disorder.

OBJECTIVE: The present study aims to examine whether declarative memory dysfunction relates to impaired core memory mechanisms or attentional and executive dysfunction in idiopathic REM Sleep Behavior Disorder (iRBD). METHOD: In this observational, cross-sectional study, were enrolled 82 individuals with the diagnosis of iRBD according to the International Classification of Sleep Disorders and 49-matched healthy controls fulfilling inclusion criteria. All participants underwent two memory tasks, namely the Rey Auditory Verbal Learning Test (RAVLT) and Memory Binding Test (MBT), which include conditions of varying degrees of dependence on executive functioning, as well as different indicators of core memory processes (e.g., learning, retention, relational binding). RESULTS: We used Bayesian multivariate generalized linear model analysis to evaluate the effect of iRBD on memory performance controlled for effects of age and sex. Individuals with iRBD displayed worse memory performance in the delayed free recall task (b = -0.37, 95% PPI [-0.69, -0.05]), but not on delayed recognition of the same material. Their performance in cued recall tasks both in immediate and delayed conditions was in comparison to controls relatively spared. Moreover, the deficit in delayed free recall was mediated by attention/processing speed. CONCLUSIONS: In iRBD, we replicated findings of reduced free recall based on inefficient retrieval (retrieval deficit), which was small in terms of effect size. Importantly, the memory profile across measures does not support the presence of core memory dysfunction, such as poor learning, retention or associative binding.

Lateralized Subthalamic Stimulation for Axial Dysfunction in Parkinson's Disease: A Randomized Trial.

BACKGROUND: Patients with Parkinson's disease might develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation. OBJECTIVES: To study whether lateralized stimulation (unilateral 50% amplitude reduction) for ≥21 days results in ≥0.13 m/s faster gait velocity in the dopaminergic ON state in these patients, and its effects on motor and axial function, quantitative gait and speech measures, quality of life, and selected cognitive tasks. METHODS: Randomized, double-blinded, double-crossover trial. RESULTS: In 22 participants (51-79 years old, 15 women), there were no significant changes in gait velocity, quality of life, cognitive, and speech measures. Reducing left-sided amplitude resulted in a 2.5-point improvement in axial motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) (P = 0.005, uncorrected) and a 1.9-point improvement in the Freezing of Gait Questionnaire (P = 0.024, uncorrected). CONCLUSIONS: Lateralized subthalamic stimulation does not result in meaningful improvement in gait velocity in patients with Parkinson's disease who develop treatment-resistant axial dysfunction after bilateral subthalamic stimulation. Left subthalamic overstimulation may contribute to axial deterioration in these patients. © 2022 International Parkinson and Movement Disorder Society.

Axial Impairment Following Deep Brain Stimulation in Parkinson's Disease: A Surgicogenomic Approach.

BACKGROUND: Postoperative outcome following deep brain stimulation (DBS) of the subthalamic nucleus is variable, particularly with respect to axial motor improvement. We hypothesized a genetic underpinning to the response to surgical intervention, termed "surgicogenomics". OBJECTIVE: We aimed to identify genetic variants associated with clinical heterogeneity in DBS outcome of Parkinson's disease (PD) patients that could then be applied clinically to target selection leading to improved surgical outcome. METHODS: Retrospective clinical data was extracted from 150 patient's charts. Each individual was genotyped using the genome-wide NeuroX array tailored to study neurologic diseases. Genetic data were clustered based on surgical outcome assessed by comparing pre- and post-operative scores of levodopa equivalent daily dose and axial impairment at one and five years post-surgery. Allele frequencies were compared between patients with excellent vs. moderate/poor outcomes grouped using a priori defined cut-offs. We analyzed common variants, burden of rare coding variants, and PD polygenic risk score. RESULTS: NeuroX identified 2,917 polymorphic markers at 113 genes mapped to known PD loci. The gene-burden analyses of 202 rare nonsynonymous variants suggested a nominal association of axial impairment with 14 genes (most consistent with CRHR1, IP6K2, and PRSS3). The strongest association with surgical outcome was detected between a reduction in levodopa equivalent daily dose and common variations tagging two linkage disequilibrium blocks with SH3GL2. CONCLUSION: Once validated in independent populations, our findings may be implemented to improve patient selection for DBS in PD.

Single-Trajectory Multiple-Target Deep Brain Stimulation for Parkinsonian Mobility and Cognition.

BACKGROUND: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is an emerging target to potentially treat cognitive dysfunction. OBJECTIVES: The aim of this study is to achieve feasibility and safety of globus pallidus pars interna (GPi) and NBM DBS in advanced PD with cognitive impairment. METHODS: We performed a phase-II double-blind crossover pilot trial in six participants to assess safety and cognitive measures, the acute effect of NBM stimulation on attention, motor and neuropsychological data at one year, and neuroimaging biomarkers of NBM stimulation. RESULTS: NBM DBS was well tolerated but did not improve cognition. GPi DBS improved dyskinesia and motor fluctuations (P = 0.04) at one year. NBM stimulation was associated with reduced right frontal and parietal glucose metabolism (P < 0.01) and increased low- and high-frequency power and functional connectivity. Volume of tissue activated in the left NBM was associated with stable cognition (P < 0.05). CONCLUSIONS: Simultaneous GPi and NBM stimulation is safe and improves motor complications. NBM stimulation altered neuroimaging biomarkers but without lasting cognitive improvement. © 2021 International Parkinson and Movement Disorder Society.

Neurophysiological responses of globus pallidus internus during the auditory oddball task in Parkinson's disease.

Parkinson's disease can be associated with significant cognitive impairment that may lead to dementia. Deep brain stimulation (DBS) of the subthalamic nucleus is an effective therapy for motor symptoms but is associated with cognitive decline. DBS of globus pallidus internus (GPi) poses less risk of cognitive decline so may be the preferred target. A research priority is to identify biomarkers of cognitive decline in this population, but efforts are hampered by a lack of understanding of the role of the different basal ganglia nuclei, such as the globus pallidus, in cognitive processing. During deep brain stimulation (DBS) surgery, we monitored single units, beta oscillatory LFP activity as well as event related potentials (ERPs) from the globus pallidus internus (GPi) of 16 Parkinson's disease patients, while they performed an auditory attention task. We used an auditory oddball task, during which one standard tone is presented at regular intervals and a second deviant tone is presented with a low probability that the subject is requested to count and report at the end of the task. All forms of neuronal activity studied were selective modulated by the attended tones. Of 62 neurons studied, the majority (51 or 82%) responded selectively to the deviant tone. Beta oscillatory activity showed an overall desynchronization during both types of attended tones interspersed by bursts of beta activity giving rise to peaks at a latency of around 200 ms after tone onset. cognitive ERPs recorded in GPi were selective to the attended tone and the right-side cERP was larger than the left side. The averages of trials showing a difference in beta oscillatory activity between deviant and standard also had a significant difference in cERP amplitude. In one block of trials, the random occurrence of 3 deviant tones in short succession silenced the activity of the GPi neuron being recorded. Trial blocks where a clear difference in LFP beta was seen were twice as likely to yield a correct tone count (25 vs 11). The data demonstrate strong modulation of GPi neuronal activity during the auditory oddball task. Overall, this study demonstrates an involvement of GPi in processing of non-motor cognitive tasks such as working memory and attention, and suggests that direct effects of DBS in non-motor GPi may contribute to cognitive changes observed post-operatively.

Multiculturalism: A Challenge for Cognitive Screeners in Parkinson's Disease.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) and the Dementia Rating Scale-2 (DRS-2) are recommended screeners for Parkinson's disease mild cognitive impairment (PD-MCI). Cross-cultural studies examining their diagnostic precision have not addressed cultural bias in a multicultural setting. OBJECTIVES: To compare DRS-2 and MoCA performance between patients born in Canada, the USA, and the UK (Anglosphere group) and immigrant patients born elsewhere (International group). To identify sources of cultural bias by comparing group characteristics, and by assessing the relationships between performance and immigration and socio-development variables. To examine the diagnostic precision of both tools in detecting PD-MCI in each group. METHODS: We conducted a clinical chart review of advanced PD patients who completed cognitive screeners (MoCA: n = 288, 30% International group; DRS-2: n = 426, 31% International group). All completed a comprehensive neuropsychological assessment to apply Level II PD-MCI diagnostic criteria. RESULTS: The International group performed worse than the Anglosphere group on the MoCA and DRS-2, and the only variable that accounted for some of the group difference was the Historical Index of Human Development, a societal variable, which fully mediated the group effect on the DRS-2. Diagnostic precision of the MoCA was at chance level in the International group, and was poorer than that of the DRS-II in this group and that of the MoCA in the Anglosphere group, although these were considered poor. CONCLUSIONS: Our results support the recommendation to exert caution in using cognitive screeners to capture PD-MCI in all patients and particularly with first generation immigrants.

Altruism in Parkinson's disease.

Objective: Reward-based decision-making is a growing area of research in Parkinson's disease (PD), a disorder characterized by alterations in dopamine and cortico-striatal circuits. While reward is typically operationalized as a gain, altruistic decisions also engage the reward system in fMRI studies. Although altruism comes at a cost, individuals may be motivated by the social reward associated with benefitting another. At present, it is unclear how PD affects altruism because both increased egoistic tendencies and increased generosity have been documented. Method: To address this, 32 individuals with PD and 32 age-matched healthy controls completed two tasks of implicit and explicit altruism. First, in an intertemporal choice task, participants chose between a smaller immediate or larger later outcome. Outcome types included gains, losses, and donations, and an implicit altruism measure was derived. Second, participants completed two versions of the dictator game, which assesses nonreciprocal giving and yields an explicit measure of altruism. Results: Patients and controls showed similar altruism in the intertemporal choice task and in a dictator game for a charity, but patients were more generous than controls in the dictator game in which the recipient was a stranger. Among patients, altruism measures were moderated by laterality of hemispheric burden and medication type. Conclusions: This study was the first to examine altruistic decision-making in PD patients using both implicit and explicit measures. PD patients were neither overly generous nor egoistic in their decisions, although some disease and treatment characteristics may have a modest association with altruism in PD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Screening for Cognitive Dysfunction Using the Rowland Universal Dementia Assessment Scale in Adults With Sickle Cell Disease.

Importance: Adults with sickle cell disease (SCD) disproportionally experience early cognitive decline; however, guidance on the optimal screening strategy for cognitive dysfunction is lacking, and several available tools are biased by language, educational level, socioeconomic status, and race/ethnicity. The Rowland Universal Dementia Assessment Scale (RUDAS) was specifically designed for cognitive screening in multicultural populations. Objective: To ascertain the prevalence of suspected dementia in adults with SCD using the RUDAS, and to identify whether age, sex, educational level, several biological variables, and SCD complications were associated with RUDAS scores. Design, Setting, and Participants: This multicenter, bilingual, cross-sectional study was conducted in 2 SCD comprehensive care centers in Canada (Centre Hospitalier de l'Université Montréal in Montréal and University Health Network in Toronto). Participants were adults aged 18 years or older and were enrolled in the study between July 1, 2018, and July 30, 2019. All outpatients were eligible and offered study participation, unless they had an acute medical condition that required inpatient care or they were unable to follow study instructions. Interventions: The RUDAS was administered by trained personnel in either French or English, according to the patient's language preference. A questionnaire on social determinants of health was also administered, and participants underwent screening for anxiety and depression. Main Outcomes and Measures: Proportion of participants with RUDAS scores that were suggestive of dementia and the RUDAS score. Any score lower than 23 points was suggestive of dementia, a score between 23 and 27 points indicated a possible association with mild neurocognitive disorder, and a score higher than 27 points was normal. Results: A total of 252 adult patients with SCD were included (136 women [54.0%]; mean [range] age, 34.8 [18-75] years). Overall, 29 patients (11.5%) had RUDAS scores that were suggestive of dementia, and this proportion increased with age (15 [8.7%] in the 18-39 years age group, 10 [14.5%] in the 40-59 years age group, and 4 [36.4%] in the ≥60 years age group). The RUDAS scores were not associated with sex, language, SCD genotype, and SCD complications. The highest level of education was significantly associated with the RUDAS score; however, the association was small (η2 = 0.02; 95% CI, 0.00-0.07; P = .02). In a multivariable analysis, lower glomerular filtration rate (r = 0.40; 95% CI, 0.29-0.50; P < .001) and increasing age (r = -0.37; 95% CI, -0.47 to -0.26; P < .001), but not SCD genotype or disease severity, were associated with lower RUDAS scores. Conclusions and Relevance: This study found that using the RUDAS revealed a high prevalence of suspected dementia in adult patients with SCD that was associated with worsening kidney function and age. Cognition should be screened in all adult patients with SCD, regardless of age, disease severity, and SCD genotype; further validation of the RUDAS is ongoing.

Acute low frequency dorsal subthalamic nucleus stimulation improves verbal fluency in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder that results in movement-related dysfunction and has variable cognitive impairment. Deep brain stimulation (DBS) of the dorsal subthalamic nucleus (STN) has been shown to be effective in improving motor symptoms; however, cognitive impairment is often unchanged, and in some cases, worsened particularly on tasks of verbal fluency. Traditional DBS strategies use high frequency gamma stimulation for motor symptoms (∼130 Hz), but there is evidence that low frequency theta oscillations (5-12 Hz) are important in cognition. METHODS: We tested the effects of stimulation frequency and location on verbal fluency among patients who underwent STN DBS implantation with externalized leads. During baseline cognitive testing, STN field potentials were recorded and the individual patients' peak theta frequency power was identified during each cognitive task. Patients repeated cognitive testing at five different stimulation settings: no stimulation, dorsal contact gamma (130 Hz), ventral contact gamma, dorsal theta (peak baseline theta) and ventral theta (peak baseline theta) frequency stimulation. RESULTS: Acute left dorsal peak theta frequency STN stimulation improves overall verbal fluency compared to no stimulation and to either dorsal or ventral gamma stimulation. Stratifying by type of verbal fluency probes, verbal fluency in episodic categories was improved with dorsal theta stimulation compared to all other conditions, while there were no differences between stimulation conditions in non-episodic probe conditions. CONCLUSION: Here, we provide evidence that dorsal STN theta stimulation may improve verbal fluency, suggesting a potential possibility of integrating theta stimulation into current DBS paradigms to improve cognitive outcomes.

Cognitive effects of theta frequency bilateral subthalamic nucleus stimulation in Parkinson's disease: A pilot study.

BACKGROUND: There is significant evidence for cognitive decline following deep brain stimulation (DBS). Current stimulation paradigms utilize gamma frequency stimulation for optimal motor benefits; however, little has been done to optimize stimulation parameters for cognition. Recent evidence implicates subthalamic nucleus (STN) theta oscillations in executive function, and theta oscillations are well-known to relate to episodic memory, suggesting that theta frequency stimulation could potentially improve cognition in Parkinson's disease (PD). OBJECTIVE: To evaluate the acute effects of theta frequency bilateral STN stimulation on executive function in PD versus gamma frequency and off, as well as investigate the differential effects on episodic versus nonepisodic verbal fluency. METHODS: Twelve patients (all males, mean age 60.8) with bilateral STN DBS for PD underwent a double-blinded, randomized cognitive testing during stimulation at (1) 130-135 Hz (gamma), (2) 10 Hz (theta) and (3) off. Executive functions and processing speed were evaluated using verbal fluency tasks (letter, episodic category, nonepisodic category, and category switching), color-word interference task, and random number generation task. Performance at each stimulation frequency was compared within subjects. RESULTS: Theta frequency significantly improved episodic category fluency compared to gamma, but not compared to off. There were no significant differences between stimulation frequencies in other tests. CONCLUSION: In this pilot trial, our results corroborate the role of theta oscillations in episodic retrieval, although it is unclear whether this reflects direct modulation of the medial temporal lobe and whether similar effects can be found with more canonical memory paradigms. Further work is necessary to corroborate our findings and investigate the possibility of interleaving theta and gamma frequency stimulation for concomitant motor and cognitive effects.

Neuromodulation for major depressive disorder: innovative measures to capture efficacy and outcomes.

Major depressive disorder is a common and debilitating disorder. Although most patients with this disorder benefit from established treatments, a subset of patients have symptoms that remain treatment resistant. Novel treatment approaches, such as deep brain stimulation, are urgently needed for patients with treatment-resistant major depressive disorder. These novel treatments are currently being tested in clinical trials in which success hinges on how accurately and comprehensively the primary outcome measure captures the treatment effect. In this Personal View, we argue that current measures used to assess outcomes in neurosurgical trials of major depressive disorder might be missing clinically important treatment effects. A crucial problem of continuing to use suboptimal outcome measures is that true signals of efficacy might be missed, thereby disqualifying potentially effective treatments. We argue that a re-evaluation of how outcomes are measured in these trials is much overdue and describe several novel approaches that attempt to better capture meaningful change.

Slowed Temporal and Parietal Cerebrovascular Response in Patients with Alzheimer's Disease.

BACKGROUND: Recent investigations now suggest that cerebrovascular reactivity (CVR) is impaired in Alzheimer's disease (AD) and may underpin part of the disease's neurovascular component. However, our understanding of the relationship between the magnitude of CVR, the speed of cerebrovascular response, and the progression of AD is still limited. This is especially true in patients with mild cognitive impairment (MCI), which is recognized as an intermediate stage between normal aging and dementia. The purpose of this study was to investigate AD and MCI patients by mapping repeatable and accurate measures of cerebrovascular function, namely the magnitude and speed of cerebrovascular response (τ) to a vasoactive stimulus in key predilection sites for vascular dysfunction in AD. METHODS: Thirty-three subjects (age range: 52-83 years, 20 males) were prospectively recruited. CVR and τ were assessed using blood oxygen level-dependent MRI during a standardized carbon dioxide stimulus. Temporal and parietal cortical regions of interest (ROIs) were generated from anatomical images using the FreeSurfer image analysis suite. RESULTS: Of 33 subjects recruited, 3 individuals were excluded, leaving 30 subjects for analysis, consisting of 6 individuals with early AD, 11 individuals with MCI, and 13 older healthy controls (HCs). τ was found to be significantly higher in the AD group compared to the HC group in both the temporal (p = 0.03) and parietal cortex (p = 0.01) following a one-way ANCOVA correcting for age and microangiopathy scoring and a Bonferroni post-hoc correction. CONCLUSION: The study findings suggest that AD is associated with a slowing of the cerebrovascular response in the temporal and parietal cortices.