Effect of rs1063843 in the CAMKK2 gene on the dorsolateral prefrontal cortex

Recently, a single nucleotide polymorphism (SNP) in the CAMKK2 gene (rs1063843) was found to be associated with lower expression of the gene in the dorsolateral prefrontal cortex (DLPFC) and with schizophrenia (SCZ) and deficits in working memory and executive function. However, the brain mechanism underlying this association is poorly understood. A functional magnetic resonance imaging (fMRI) study (N = 84 healthy volunteers) involving multiple cognitive tasks, including a Stroop task (to measure attentional executive control), an N‐back task (to measure working memory), and a delay discounting task (to measure decision making) to identify the brain regions affected by rs1063843 was performed. Across all three tasks, it was found that carriers of the risk allele consistently exhibited increased activation of the left DLPFC. In addition, the risk allele carriers also exhibited increased activation of the right DLPFC and the left cerebellum during the Stroop task and of the left caudate nucleus during the N‐back task. These findings helped to elucidate the role of CAMKK2 in cognitive functions and in the etiology of SCZ. Hum Brain Mapp 37:2398–2406, 2016. © 2016 Wiley Periodicals, Inc .     

Network abnormalities among non‐manifesting Parkinson disease related LRRK2 mutation carriers

Non‐manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an “at risk” group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting‐state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (D_EPNA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty‐four NMC and 41 non‐manifesting non‐carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non‐motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non‐motor cerebral changes among populations “at risk” for future development of PD.     

The effects of rasagiline on cognitive deficits in Parkinson's disease patients without dementia: A randomized,double‐blind,placebo‐controlled,multicenter study

Cognitive impairment can occur at all stages of Parkinson's disease. Rasagiline is a selective monoamine oxidase type‐B inhibitor that enhances central dopaminergic transmission. Dopamine is thought to be involved in certain cognitive processes such as working memory. We assessed the effects of rasagiline on cognitive deficits in cognitively impaired, nondemented patients with Parkinson's disease. This was a randomized, double‐blind, placebo‐controlled prospective study. Patients with Parkinson's disease receiving stable dopaminergic treatment were assigned to receive rasagiline 1 mg/day or placebo for 3 months. Patients were eligible if they had impairment in 2 of 4 cognitive domains (attention, executive functions, memory, visuospatial functions) in the screening neuropsychological tests, yet did not fulfill criteria for Parkinson's disease dementia. Fifty‐five patients were randomized; 48 patients completed the study. Patients in the rasagiline group showed significant improvement in digit span–backward compared with the placebo group (P = .04), with trends favoring rasagiline in digit span total and digit‐ordering tests. Verbal fluency total score showed a significant difference in favor of rasagiline (P = .038), with trends favoring rasagiline in semantic fluency test and Stroop spontaneous corrections. The composite cognitive domain Z scores revealed a significant difference in favor of rasagiline compared with placebo in the attentional Z score (P < .005). There were no significant differences between the 2 groups in the other cognitive tests or cognitive domain Z scores. The monoamine oxidase type‐B inhibitor rasagiline may exert beneficial effects on certain aspects of attention and executive functions in nondemented patients with Parkinson's disease with cognitive impairment. © 2011 Movement Disorder Society     

Cognitive and psychiatric symptoms in genetically determined Parkinson’s disease: a systematic review

The aim was to review the existing reports on cognitive and behavioural symptoms in monogenic forms of Parkinson’s disease (PD) and to identify recurring patterns of clinical manifestations in those with specific mutations. A systematic literature search was conducted to retrieve observational studies of monogenic PD. Data pertaining to cognitive and psychiatric manifestations were extracted using standardized templates. The PRISMA guidelines were followed. Of the 1889 citations retrieved, 95 studies on PD‐related gene mutations were included: 35 in SNCA, 35 in LRRK2, four in VPS35, 10 in Parkin, three in DJ1 and eight in PINK1. Nineteen studies (20%) provided adequate data from comprehensive cognitive assessment and 31 studies (32.6%) outlined psychiatric manifestations through the use of neuropsychiatric scales. Cognitive impairment was reported in all monogenic PD forms with variable rates (58.8% PINK1, 53.9% SNCA, 50% DJ1, 29.2% VPS35, 15.7% LRRK2 and 7.4% Parkin). In this regard, executive functions and attention were the domains most affected. With respect to psychiatric symptoms, depression was the most frequent symptom, occurring in 37.5% of PINK1 cases and 41.7% of VPS35 and LRRK2 cases. Co‐occurrence of cognitive decline with visual hallucinations was evidenced. Widespread accumulation of Lewy bodies, distinctive of SNCA, PINK1 and DJ1 mutations, results in higher rates of cognitive impairment. Similarly, a higher degree of visual hallucinations is observed in SNCA mutations, probably owing to the more widespread accumulation. The lower rates of α‐synuclein pathology in LRRK2 and Parkin may underpin the more benign disease course in these patients.     

Lower cognitive performance in healthy G2019S LRRK2 mutation carriers

OBJECTIVE: To assess cognitive abilities of healthy first-degree relatives of Ashkenazi patients with Parkinson disease (PD), carriers of the G2019S mutation in the LRRK2 gene. METHODS: In this observational study, 60 consecutive healthy first-degree relatives (aged 50.9 ± 6.2 years; 48% male; 30 G2019S carriers) were assessed using a computerized cognitive program, the Montreal Cognitive Assessment questionnaire, the Unified Parkinson's Disease Rating Scale Part III, and the Geriatric Depression Scale. RESULTS: G2019S carriers scored significantly lower on the computerized executive function index (p = 0.04) and on specific executive function tasks (Stroop test, p = 0.007). CONCLUSION: Carrying the LRRK2 G2019S mutation was associated with lower executive performance in a population at risk for PD.     

Olfactory deficits and cardiac 123I‐MIBG in Parkinson's disease related to the LRRK2 R1441G and G2019S mutations

It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I‐metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac ¹²³I‐metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty‐six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty‐six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2. © 2011 Movement Disorder Society     

Cognitive impairment in rapid‐onset dystonia‐parkinsonism

Rapid‐onset dystonia‐parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation‐negative controls. We studied 22 familial RDP patients, 3 non‐motor‐manifesting mutation‐positive family members, 29 mutation‐negative family member controls in 9 families, and 4 unrelated RDP patients, totaling 58 individuals. We administered a movement disorder assessment, including the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) and a cognitive battery of memory and learning, psychomotor speed, attention, and executive function. The cognitive battery was designed to evaluate a wide range of functions; recognition memory instruments were selected to be relatively pure measures of delayed memory, devoid of significant motor or vocal production limitations. Comparisons of standardized cognitive scores were assessed both with and without controlling for psychomotor speed and similarly for severity of depressive symptoms. A majority of RDP patients had onset of motor symptoms by age 25 and had initial symptom presentation in the upper body (face, mouth, or arm). Among patients, the BFMDRS (mean ± SD, 52.1 ± 29.5) and UPDRS motor subscore (29.8 ± 12.7) confirmed dystonia‐parkinsonism. The affected RDP patients performed more poorly, on average, than mutation‐negative controls for all memory and learning, psychomotor speed, attention, and executive function scores (all P ≤ 0.01). These differences persisted after controlling for psychomotor speed and severity of depressive symptoms. Impaired cognitive function may be a manifestation of ATP1A3 mutation and RDP. © 2014 International Parkinson and Movement Disorder Society     

Precuneus degeneration in nondemented elderly individuals with APOE ɛ4: Evidence from structural and functional MRI analyses

Neurodegenerative diseases such as Alzheimer's disease (AD) have been recognized to exhibit disease‐specific brain vulnerability patterns. Apolipoprotein E (APOE ) ?4 allele imparts a high genetic risk of developing AD. Whether the APOE ?4 allele damages the brain when cognitive functions are still intact is important to understand, especially for possible early detection and intervention. This study aimed to examine the selective degeneration pattern associated with the APOE ?4 allele in the brains of cognitively normal elderly subjects. We enrolled 35 cognitively healthy ?4 carriers and 40 non‐carriers (53 to 81 years old) to evaluate group differences in cortical thickness and brain activation during a memory‐encoding task. We also assessed the functional connectivity of the brain regions with both structural and functional damages. The results from the neuropsychological tests showed that the performances of ?4 carriers and non‐carriers were comparable. Primarily, we found that the precuneus exhibited thinner cortical thickness and decreased deactivation during memory encoding. Furthermore, the connectivity analyses show that carriers exhibited damaged connectivity of the precuneus to several regions in the default mode network and the attention/executive control network. Our study reveals the degeneration pattern of the ?4 allele, which could be used as a potential biomarker for early detection for possible interventions and treatments. Hum Brain Mapp 38:271–282, 2017 . © 2016 Wiley Periodicals, Inc.     

Computerised working memory‐based cognitive remediation therapy does not affect Reading the Mind in The Eyes test performance or neural activity during a Facial Emotion Recognition test in psychosis

Working memory‐based cognitive remediation therapy (CT) for psychosis has recently been associated with broad improvements in performance on untrained tasks measuring working memory, episodic memory and IQ, and changes in associated brain regions. However, it is unclear whether these improvements transfer to the domain of social cognition and neural activity related to performance on social cognitive tasks. We examined performance on the Reading the Mind in the Eyes test (Eyes test) in a large sample of participants with psychosis who underwent working memory‐based CT (N = 43) compared to a control group of participants with psychosis (N = 35). In a subset of this sample, we used functional magnetic resonance imaging (fMRI) to examine changes in neural activity during a facial emotion recognition task in participants who underwent CT (N = 15) compared to a control group (N = 15). No significant effects of CT were observed on Eyes test performance or on neural activity during facial emotion recognition, either at p < 0.05 family‐wise error or at a p < 0.001 uncorrected threshold, within a priori social cognitive regions of interest. This study suggests that working memory‐based CT does not significantly impact an aspect of social cognition which was measured behaviourally and neurally. It provides further evidence that deficits in the ability to decode mental state from facial expressions are dissociable from working memory deficits, and suggests that future CT programmes should target social cognition in addition to working memory for the purposes of further enhancing social function.     

Effect of baseline cannabis use and working‐memory network function on changes in cannabis use in heavy cannabis users: A prospective fMRI study

Theoretical models of addiction suggest that a substance use disorder represents an imbalance between hypersensitive motivational processes and deficient regulatory executive functions. Working‐memory (a central executive function) may be a powerful predictor of the course of drug use and drug‐related problems. Goal of the current functional magnetic resonance imaging study was to assess the predictive power of working‐memory network function for future cannabis use and cannabis‐related problem severity in heavy cannabis users. Tensor independent component analysis was used to investigate differences in working‐memory network function between 32 heavy cannabis users and 41 nonusing controls during an N‐back working‐memory task. In addition, associations were examined between working‐memory network function and cannabis use and problem severity at baseline and at 6‐month follow‐up. Behavioral performance and working‐memory network function did not significantly differ between heavy cannabis users and controls. However, among heavy cannabis users, individual differences in working‐memory network response had an independent effect on change in weekly cannabis use 6 months later (ΔR² = 0.11, P = 0.006, f² = 0.37) beyond baseline cannabis use (ΔR² = 0.41) and a behavioral measure of approach bias (ΔR² = 0.18): a stronger network response during the N‐back task was related to an increase in weekly cannabis use. These findings imply that heavy cannabis users requiring greater effort to accurately complete an N‐back working‐memory task have a higher probability of escalating cannabis use. Working‐memory network function may be a biomarker for the prediction of course and treatment outcome in cannabis users. Hum Brain Mapp 35:2470–2482, 2014. © 2013 Wiley Periodicals, Inc .     

Reduced neural connectivity but increased task‐related activity during working memory in de novo Parkinson patients

Objective: Patients with Parkinson's disease (PD) often suffer from impairments in executive functions, such as working memory deficits. It is widely held that dopamine depletion in the striatum contributes to these impairments through decreased activity and connectivity between task‐related brain networks. We investigated this hypothesis by studying task‐related network activity and connectivity within a sample of de novo patients with PD, versus healthy controls, during a visuospatial working memory task. Methods: Sixteen de novo PD patients and 35 matched healthy controls performed a visuospatial n‐back task while we measured their behavioral performance and neural activity using functional magnetic resonance imaging. We constructed regions‐of‐interest in the bilateral inferior parietal cortex (IPC), bilateral dorsolateral prefrontal cortex (DLPFC), and bilateral caudate nucleus to investigate group differences in task‐related activity. We studied network connectivity by assessing the functional connectivity of the bilateral DLPFC and by assessing effective connectivity within the frontoparietal and the frontostriatal networks. Results: PD patients, compared with controls, showed trend‐significantly decreased task accuracy, significantly increased task‐related activity in the left DLPFC and a trend‐significant increase in activity of the right DLPFC, left caudate nucleus, and left IPC. Furthermore, we found reduced functional connectivity of the DLPFC with other task‐related regions, such as the inferior and superior frontal gyri, in the PD group, and group differences in effective connectivity within the frontoparietal network. Interpretation: These findings suggest that the increase in working memory‐related brain activity in PD patients is compensatory to maintain behavioral performance in the presence of network deficits. Hum Brain Mapp 36:1554–1566, 2015. © 2015 Wiley Periodicals, Inc.     

Fall risk and gait in Parkinson's disease: The role of the LRRK2 G2019S mutation

Patients with Parkinson's disease (PD) who carry the G2019S mutation (a glycine to serine substitution at amino acid 2019) in the leucine‐rich repeat kinase 2 (LRRK2) gene are generally believed to be clinically indistinguishable from patients with sporadic PD. There are, however, conflicting reports on the relationship between the mutation and the motor phenotype. We quantitatively compared gait and mobility in patients with PD carriers of the G2019S mutation to non‐carrier patients with PD to better understand the genotype‐phenotype relationship. Fifty patients with PD carriers of the G2019S LRRK2 mutation and 50 age, disease duration, and disease severity matched PD non‐carriers were studied. An accelerometer quantified gait under three walking conditions: usual‐walking, dual‐tasking, and fast‐walking. The Unified Parkinson's Disease Rating Scale classified patients into PD sub‐types and the Timed Up and Go quantified mobility and fall risk. In all three walking conditions, gait variability was larger and the walking pattern was less consistent among the PD mutation carriers (P < 0.016). The PD carriers also took longer to complete the Timed Up and Go (P = 0.011) and were more likely to report having fallen in the previous year (P = 0.018). 64% of the PD carriers were classified as belonging to the postural‐instability‐gait‐difficulty (PIGD) sub‐type compared to only 17% of the PD non‐carriers (P < 0.0001). Among patients with PD, the G2019S mutation in the LRRK2 gene is apparently associated with increased gait variability, an increased fall risk, and the PIGD sub‐type. Therapeutic approach specifically designed to delay gait disturbances and falls may be justified in patients who carry the G2019S mutation. © 2013 International Parkinson and Movement Disorder Society     

Subtle Executive Impairment in Children with Autism and Children with ADHD

Background: The executive functions of inhibition, planning, flexible shifting of actions, and working memory are commonly reported to be impaired in neurodevelopmental disorders. Method: We compared these abilities in children (8–12 years) with high functioning autism (HFA, n = 17), attention deficit-hyperactivity disorder (ADHD, n = 21) and healthy controls (n = 32). Response inhibition was assessed using the Stroop Color and Word Test (Golden, 1978). Problem solving, set-shifting, and nonverbal memory were assessed using three tasks, respectively, from the CANTAB^® (Cambridge Cognition, 1996): the Stockings of Cambridge task; the Intra-Dimensional/Extra-Dimensional set-shifting task; and the Spatial Working Memory task (SWM) with tokens hidden behind 3, 4, 6, and 8 boxes. Results: There were no group differences on the response inhibition, planning, or set-shifting tasks. On the SWM task, children with HFA made significantly more between-searcherrors compared with controls on both the most difficult problems (8-box) and on the mid-difficulty problems (6-box); however, children with ADHD made significantly more errors compared to controls on the most difficult (8-box) problems only. Conclusion: Our findings suggest that spatial working memory is impaired in both ADHD and HFA, and more severely in the latter. More detailed investigation is needed to examine the mechanisms that differentially impair spatial working memory, but on this set of tasks there appears to be sparing of other executive functions in these neuropsychiatric developmental disorders.     

Cognitive dysfunction in Tunisian LRRK2 associated Parkinson's disease

BackgroundCognitive impairment and dementia are frequent and debilitating features associated with idiopathic Parkinson’s disease (PD). However the prevalence and the pattern of these complications are lacking for LRRK2 (leucine-rich kinase 2)-associated PD patients.PurposeThe purpose of this study was to assess cognitive function in LRRK2- associated PD patients.Material and methods55 patients diagnosed with PD-related LRRK2 G2019S mutation were included in the study and compared to the same number of G2019S non-carriers PD patients. Age, sex, disease duration, the movement disorder society-unified Parkinson’s Disease rating scale (MDS-UPDRS), Hoehn and Yahr stage, Schwab and England scale and the 30-item geriatric depression scale (GDS) scores were noted. Cognitive assessment included MMSE (Mini-Mental Examination), MOCA (Montreal Cognitive Assessment) and FAB (Frontal Assessment Battery).ResultsMMSE, MOCA and FAB performance in G2019S carriers PD patients was similar to that of non-carriers. In both groups, performance was primarily impaired on visuospatial and executive tasks. Cognitive impairment was associated with older age, lower educational level and increased severity of motor impairment.ConclusionCognitive functions were similarly affected in PD patients with and without LRRK2 G2019S mutation with mainly impaired visuospatial and executive abilities. However, these results need to be confirmed by further large and prospective studies.     

APOE influences working memory in non‐demented elderly through an interaction with SPON1 rs2618516

Exploring how risk genes cumulatively impair brain function in preclinical phase (i.e., in cognitively normal elderly) could provide critical insights into the pathophysiology of Alzheimer's disease (AD). Working memory impairment has always been a considerable cognitive deficit in AD, which is likely under complex genetic control. Though, the APOE ?4 allele could damage the working memory performance in normal elderly, dissociable results have been reported. This allele may exert specific effects in contexts with other genetic variants. The rs2618516 in the spondin 1 gene (SPON1) has been associated with AD risk and brain structure in the elderly. SPON1 may interact with APOE through processing the amyloid precursor protein and suppressing amyloid‐β levels. Using neuropsychological tasks from 710 individuals, we found significant SPON1 × APOE genotype interactions in working memory and executive function performances. Moreover, such interaction was also found in regional brain activations based on functional magnetic resonance imaging data with the n‐back working memory task performed in a sub‐cohort of 64 subjects. The effects of ?4 allele on activation of right inferior frontal gyrus, triangular part (IFGtriang.R) were modulated by rs2618516 in a working memory task. Furthermore, lower IFGtriang.R activation was associated with better cognitive functions. Moreover, the IFGtriang.R activation could mediate the impacts of SPON1 × APOE interactions on working memory performance. These findings suggested the importance of weighing APOE effects on brain activation under the working memory task within the context of the SPON1 genotype.     

Toward a “treadmill test” for cognition: Improved prediction of general cognitive ability from the task activated brain

General cognitive ability (GCA) refers to a trait‐like ability that contributes to performance across diverse cognitive tasks. Identifying brain‐based markers of GCA has been a longstanding goal of cognitive and clinical neuroscience. Recently, predictive modeling methods have emerged that build whole‐brain, distributed neural signatures for phenotypes of interest. In this study, we employ a predictive modeling approach to predict GCA based on fMRI task activation patterns during the N‐back working memory task as well as six other tasks in the Human Connectome Project dataset (n = 967), encompassing 15 task contrasts in total. We found tasks are a highly effective basis for prediction of GCA: The 2‐back versus 0‐back contrast achieved a 0.50 correlation with GCA scores in 10‐fold cross‐validation, and 13 out of 15 task contrasts afforded statistically significant prediction of GCA. Additionally, we found that task contrasts that produce greater frontoparietal activation and default mode network deactivation—a brain activation pattern associated with executive processing and higher cognitive demand—are more effective in the prediction of GCA. These results suggest a picture analogous to treadmill testing for cardiac function: Placing the brain in a more cognitively demanding task state significantly improves brain‐based prediction of GCA.     

Duration effect of obsessive–compulsive disorder on cognitive function: a functional MRI study

Background: The inconsistency of previous reports examining cognitive function in obsessive–compulsive disorder (OCD) suggests its heterogeneity. In this study, we examined the effect of illness duration on cognitive function in OCD. Methods: We examined the cognitive function of 32 OCD patients and 16 healthy volunteers by neuropsychological tests and functional magnetic resonance imaging while they performed the Stroop and N‐back tasks to assess attention and nonverbal memory. The patients were divided into two groups by illness duration: a short‐term group (n=17, 5.5±3.1 years) and a long‐term group (n=15, 20.3±6.1 years). Statistical analysis was performed to determine the differences between these two groups and the normal control group (n=16). Results: The long‐term group showed attention deficit and nonverbal memory dysfunction on the neuropsychological tests. In contrast, on functional magnetic resonance imaging, the short‐term group showed weaker activation of the right caudate during the Stroop task and stronger activation of the right dorso‐lateral prefrontal cortex during the N‐back task than the long‐term and normal control groups. Conclusions: The results suggested that abnormal brain activation occurs in the early phase of OCD and that the long‐term persistence of OCD might involve a decline in cognitive function. Depression and Anxiety, 2009. © 2008 Wiley‐Liss, Inc.     

A meta‐analysis of cerebellar contributions to higher cognition from PET and fMRI studies

A growing interest in cerebellar function and its involvement in higher cognition have prompted much research in recent years. Cerebellar presence in a wide range of cognitive functions examined within an increasing body of neuroimaging literature has been observed. We applied a meta‐analytic approach, which employed the activation likelihood estimate method, to consolidate results of cerebellar involvement accumulated in different cognitive tasks of interest and systematically identified similarities among the studies. The current analysis included 88 neuroimaging studies demonstrating cerebellar activations in higher cognitive domains involving emotion, executive function, language, music, timing and working memory. While largely consistent with a prior meta‐analysis by Stoodley and Schmahmann ( 2009 : Neuroimage 44:489‐501), our results extended their findings to include music and timing domains to provide further insights into cerebellar involvement and elucidate its role in higher cognition. In addition, we conducted inter‐ and intradomain comparisons for the cognitive domains of emotion, language, and working memory. We also considered task differences within the domain of verbal working memory by conducting a comparison of the Sternberg with the n‐back task, as well as an analysis of the differential components within the Sternberg task. Results showed a consistent cerebellar presence in the timing domain, providing evidence for a role in time keeping. Unique clusters identified within the domain further refine the topographic organization of the cerebellum. Hum Brain Mapp 35:593–615, 2014. © 2012 Wiley Periodicals, Inc.     

Quiet connections: Reduced fronto‐temporal connectivity in nondemented Parkinson's Disease during working memory encoding

Parkinson's disease (PD) is a common neurodegenerative disorder characterized primarily by motor symptoms such as bradykinesia, muscle rigidity, and resting tremor. It is now broadly accepted that these motor symptoms frequently co‐occur with cognitive impairments, with deficits in working memory and attention being among the most common cognitive sequelae associated with PD. While these cognitive impairments are now recognized, the underlying neural dynamics and precise regions involved remain largely unknown. To this end, we examined the oscillatory dynamics and interregional functional connectivity that serve working memory processing in a group of unmedicated adults with PD and a matched group without PD. Each participant completed a high‐load, Sternberg‐type working memory task during magnetoencephalography (MEG), and we focused on the encoding and maintenance phases. All data were transformed into the time–frequency domain and significant oscillatory activity was imaged using a beamforming approach. Phase‐coherence (connectivity) was also computed among the brain subregions exhibiting the strongest responses. Our most important findings were that unmedicated patients with PD had significantly diminished working memory performance (i.e., accuracy), and reduced functional connectivity between left inferior frontal cortices and left supramarginal–superior temporal cortices compared to participants without PD during the encoding phase of working memory processing. We conclude that patients with PD have reduced neural interactions between left prefrontal executive circuits and temporary verbal storage centers in the left supramarginal/superior temporal cortices during the stimulus encoding phase, which may underlie their diminished working memory function. Hum Brain Mapp 37:3224–3235, 2016. © 2016 Wiley Periodicals, Inc.