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.     

Load effects on spatial working memory performance are linked to distributed alpha and beta oscillations

Increasing spatial working memory (SWM) load is generally associated with declines in behavioral performance, but the neural correlates of load‐related behavioral effects remain poorly understood. Herein, we examine the alterations in oscillatory activity that accompany such performance changes in 22 healthy adults who performed a two‐ and four‐load SWM task during magnetoencephalography (MEG). All MEG data were transformed into the time‐frequency domain and significant oscillatory responses were imaged separately per load using a beamformer. Whole‐brain correlation maps were computed using the load‐related beamformer difference images and load‐related accuracy effects on the SWM task. The results indicated that load‐related differences in left inferior frontal alpha activity during encoding and maintenance were negatively correlated with load‐related accuracy differences on the SWM task. That is, individuals who had more substantial decreases in prefrontal alpha during high‐relative to low‐load SWM trials tended to have smaller performance decrements on the high‐load condition (i.e., they performed more accurately). The same pattern of neurobehavioral correlations was observed during the maintenance period for right superior temporal alpha activity and right superior parietal beta activity. Importantly, this is the first study to employ a voxel‐wise whole‐brain approach to significantly link load‐related oscillatory differences and load‐related SWM performance differences.     

Male veterans with PTSD exhibit aberrant neural dynamics during working memory processing: an MEG study

BackgroundPosttraumatic stress disorder (PTSD) is associated with executive functioning deficits, including disruptions in working memory. In this study, we examined the neural dynamics of working memory processing in veterans with PTSD and a matched healthy control sample using magnetoencephalography (MEG).MethodsOur sample of recent combat veterans with PTSD and demographically matched participants without PTSD completed a working memory task during a 306-sensor MEG recording. The MEG data were preprocessed and transformed into the time-frequency domain. Significant oscillatory brain responses were imaged using a beamforming approach to identify spatiotemporal dynamics.ResultsFifty-one men were included in our analyses: 27 combat veterans with PTSD and 24 controls. Across all participants, a dynamic wave of neural activity spread from posterior visual cortices to left frontotemporal regions during encoding, consistent with a verbal working memory task, and was sustained throughout maintenance. Differences related to PTSD emerged during early encoding, with patients exhibiting stronger α oscillatory responses than controls in the right inferior frontal gyrus (IFG). Differences spread to the right supramarginal and temporal cortices during later encoding where, along with the right IFG, they persisted throughout the maintenance period.LimitationsThis study focused on men with combat-related PTSD using a verbal working memory task. Future studies should evaluate women and the impact of various traumatic experiences using diverse tasks.ConclusionPosttraumatic stress disorder is associated with neurophysiological abnormalities during working memory encoding and maintenance. Veterans with PTSD engaged a bilateral network, including the inferior prefrontal cortices and supramarginal gyri. Right hemispheric neural activity likely reflects compensatory processing, as veterans with PTSD work to maintain accurate performance despite known cognitive deficits associated with the disorder.     

tDCS modulates behavioral performance and the neural oscillatory dynamics serving visual selective attention

Transcranial direct‐current stimulation (tDCS) is a noninvasive method for modulating human brain activity. Although there are several hypotheses about the net effects of tDCS on brain function, the field's understanding remains incomplete and this is especially true for neural oscillatory activity during cognitive task performance. In this study, we examined whether different polarities of occipital tDCS differentially alter flanker task performance and the underlying neural dynamics. To this end, 48 healthy adults underwent 20 min of anodal, cathodal, or sham occipital tDCS, and then completed a visual flanker task during high‐density magnetoencephalography (MEG). The resulting oscillatory responses were imaged in the time‐frequency domain using beamforming, and the effects of tDCS on task‐related oscillations and spontaneous neural activity were assessed. The results indicated that anodal tDCS of the occipital cortices inhibited flanker task performance as measured by reaction time, elevated spontaneous activity in the theta (4–7 Hz) and alpha (9–14 Hz) bands in prefrontal and occipital cortices, respectively, and reduced task‐related theta oscillatory activity in prefrontal cortices during task performance. Cathodal tDCS of the occipital cortices did not significantly affect behavior or any of these neuronal parameters in any brain region. Lastly, the power of theta oscillations in the prefrontal cortices was inversely correlated with reaction time. In conclusion, anodal tDCS modulated task‐related oscillations and spontaneous activity across multiple cortical areas, both near the electrode and in distant sites that were putatively connected to the targeted regions.     

Numerical working memory alters alpha‐beta oscillations and connectivity in the parietal cortices

Although the neural bases of numerical processing and memory have been extensively studied, much remains to be elucidated concerning the spectral and temporal dynamics surrounding these important cognitive processes. To further this understanding, we employed a novel numerical working memory paradigm in 28 young, healthy adults who underwent magnetoencephalography (MEG). The resulting data were examined in the time‐frequency domain prior to image reconstruction using a beamformer. Whole‐brain, spectrally‐constrained coherence was also employed to determine network connectivity. In response to the numerical task, participants exhibited robust alpha/beta oscillations in the bilateral parietal cortices. Whole‐brain statistical comparisons examining the effect of numerical manipulation during memory‐item maintenance revealed a difference centered in the right superior parietal cortex, such that oscillatory responses during numerical manipulation were significantly stronger than when no manipulation was necessary. Additionally, there was significantly reduced cortico‐cortical coherence between the right and left superior parietal regions during the manipulation compared to the maintenance trials, indicating that these regions were functioning more independently when the numerical information had to be actively processed. In sum, these results support previous studies that have implicated the importance of parietal regions in numerical processing, but also provide new knowledge on the spectral, temporal, and network dynamics that serve this critical cognitive function during active working memory maintenance.     

Adult age differences in the functional neuroanatomy of verbal recognition memory

Adult age differences are frequently observed in the performance of memory tasks, but the changes in neural function mediating these differences are largely unknown. We used H₂¹⁵O positron emission tomography (PET) to measure changes in regional cerebral blood flow (rCBF) during Encoding, Baseline, and Retrieval conditions of a recognition memory task. Twelve young adults (20–29 years) and 12 older adults (62–79 years) participated. During each task condition, participants made a two‐choice manual response to each of 64 words. Analyses of the performance data yielded evidence of age‐related slowing of encoding and retrieval processes, and an age‐related decline in the accuracy of yes/no recognition (d'). The rCBF activation associated with both encoding and retrieval was greater for older adults than for young adults, but this pattern was more clearly evident for memory retrieval. For young adults, rCBF activation during retrieval occurred primarily in right prefrontal cortex, whereas older adults exhibited a more bilateral pattern of prefrontal activation. Regression analyses predicting reaction time in the memory task from regional PET counts confirmed that the neural system mediating memory retrieval is more widely distributed for older adults than for young adults. Both age groups exhibited some decrease in rCBF activation in the second half of the test session, relative to the first half. The practice‐related decrease in rCBF activation was more prominent for young adults, suggesting that the older adults' recruitment of additional neural systems reflects a more continual allocation of attention to support task performance. Hum. Brain Mapping 7:115–135, 1999. © 1999 Wiley‐Liss, Inc.     

Cortical oscillations that underlie working memory are altered in adults with cerebral palsy

ObjectiveThis investigation used magnetoencephalography (MEG) to identify the neurophysiological mechanisms contributing to the altered cognition seen in adults with cerebral palsy (CP).MethodsAdults with CP (GMFCS levels I-IV) and demographically-matched controls completed a Sternberg-type working memory task during MEG. Secondarily, they completed the National Institutes of Health (NIH) cognitive toolbox. Beamforming was used to image the significant MEG oscillatory responses and the resulting images were examined using statistical parametric mapping to identify cortical activity that differed between groups.ResultsBoth groups had a left-lateralized decrease in alpha–beta (11–16 Hz) power across the occipital, temporal, and prefrontal cortices during encoding, as well as an increase in alpha (9–13 Hz) power across the occipital cortices during maintenance. The strength of alpha–beta oscillations in the prefrontal cortices were weaker in those with CP during encoding. Weaker alpha–beta oscillation within the prefrontal cortex was associated with poorer performance on the NIH toolbox and a higher GMFCS level.ConclusionsAlpha-beta aberrations may impact the basic encoding of information in adults with CP, which impacts their overall cognition. Altered alpha–beta oscillation might be connected with gross motor function.SignificanceThis experimental work highlights the aberrant alpha–beta during encoding as possible neurophysiological mechanism of the cognitive deficiencies.     

Abnormal cortical neural synchrony during working memory in schizophrenia

Objective

To better understand the origins of working memory (WM) impairment in schizophrenia we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM task requiring encoding, maintenance, and retrieval/manipulation processes of spatial information.

Age-related differences in the neural correlates of remembering time-based intentions

The present study used event-related potentials (ERPs) to explore the effect of age on the neural correlates of monitoring processes involved in time-based prospective memory. In both younger and older adults, the addition of a time-based prospective memory task to an ongoing task led to a sustained ERP activity broadly distributed over the scalp. Older adults, however, did not exhibit the slow wave activity observed in younger adults over prefrontal regions, which is considered to be associated with retrieval mode. This finding indicates that age-related decline in intention maintenance might be one source of the impaired prospective memory performance displayed by older adults. An 'anterior shift' in scalp distribution of the P3 was observed in older adults, and was related to lower levels of accuracy in prospective memory performance. This relationship suggests that possible factors responsible for age-related decline in prospective memory performance include the decreased efficiency of executive/frontal functions as well as the reduced amount of resources available for the prospective memory task.     

Dissociating age-related changes in cognitive strategy and neural efficiency using event-related fMRI

We used event-related fMRI to measure brain activity while younger and older adults performed an item-recognition task in which the memory-set size varied between 1 and 8 letters. Each trial was composed of a 4-second encoding period in which subjects viewed random letter strings, a 12-second retention period and a 2-second retrieval period in which subjects decided whether a single probe letter was or was not part of the memory set. For both groups, reaction time increased and accuracy decreased with increasing memory set-size. There were minimal age-related differences in activation patterns with increasing memory set-size in prefrontal cortex (PFC). Regression analyses of individual subjects' performance and cortical activity indicated that speed and accuracy accounted for considerable variance in dorsal and ventral PFC activity during encoding and retrieval. These results suggest that younger and older adults utilize similar working memory (WM) strategies to accommodate increasing memory demand. They support a model of cognitive slowing in which processing rate is related to neural efficiency.     

Cerebral correlates of working memory for temporal information

Studies of neural correlates of working memory functions in the auditory-verbal, visuo-spatial and visuo-object domain suggest a category-specific organization of working memory processes in prefrontal cortex. Here, we used fMRI to explore brain areas that underlie different working memory operations directed to the temporal domain, which so far has been widely neglected. Significant activations related to memory updating and comparison processes were found right-accentuated in prefrontal and lateral premotor cortices. Furthermore, both subvocal rhythm encoding and maintenance enhanced left-lateralized activity in Broca's and supplementary motor area as well as in the sensorimotor cortex. Hemispheric lateralization effects of brain activity during temporal processing tasks may depend on the presence or absence of subvocal rehearsal strategies.     

The effect of beta‐amyloid on face processing in young and old adults: A multivariate analysis of the BOLD signal

The recent ability to measure in vivo beta‐amyloid (Aβ), a marker of Alzheimer's disease (AD), has led to an increased focus on the significance of Aβ deposition in clinically normal adults. Evidence suggests that healthy adults with elevated cortical Aβ show differences in neural activity associated with memory encoding—specifically encoding of face stimuli. Here, we examined if Aβ deposition in clinically normal adults was related to differences in neural activity in ventral visual cortex during face viewing. Our sample included 23 high‐Aβ older adults, 23 demographically matched low‐Aβ older adults, and 16 young adults. Participants underwent cognitive testing, Aβ positron emission tomography imaging with ¹⁸F‐Florbetapir, and functional magnetic resonance imaging to measure neural activity while participants passively viewed photographs of faces. Using barycentric discriminant analysis—a between‐groups classification technique—we found that patterns of neural activity in the left fusiform gyrus, a region highly responsive to faces, distinguished Aβ status of participants. Older adults with elevated Aβ were characterized by decreased activity in left fusiform compared to Aβ‐negative older adults. Further, we found that the degree to which older adults expressed decreased fusiform activity was related to worse performance on tasks of processing speed. Our results provide unique evidence that, in addition to previously studied memory and default regions , decreased neural activity in a region important for face perception was associated with elevated Aβ and may be an early manifestation of AD. Hum Brain Mapp 36:2514–2526, 2015. © 2015 Wiley Periodicals, Inc .     

The role of cortical beta oscillations in time estimation

Estimation of time is central to perception, action, and cognition. Human functional magnetic resonance imaging (fMRI) and positron emission topography (PET) have revealed a positive correlation between the estimation of multi‐second temporal durations and neuronal activity in a circuit of sensory and motor areas, prefrontal and temporal cortices, basal ganglia, and cerebellum. The systems‐level mechanisms coordinating the collective neuronal activity in these areas have remained poorly understood. Synchronized oscillations regulate communication in neuronal networks and could hence serve such coordination, but their role in the estimation and maintenance of multi‐second time intervals has remained largely unknown. We used source‐reconstructed magnetoencephalography (MEG) to address the functional significance of local neuronal synchronization, as indexed by the amplitudes of cortical oscillations, in time‐estimation. MEG was acquired during a working memory (WM) task where the subjects first estimated and then memorized the durations, or in the contrast condition, the colors of dynamic visual stimuli. Time estimation was associated with stronger beta (β, 14 ? 30 Hz) band oscillations than color estimation in sensory regions and attentional cortical structures that earlier have been associated with time processing. In addition, the encoding of duration information was associated with strengthened gamma‐ (γ, 30 ? 120 Hz), and the retrieval and maintenance with alpha‐ (α, 8 ? 14 Hz) band oscillations. These data suggest that β oscillations may provide a mechanism for estimating short temporal durations, while γ and α oscillations support their encoding, retrieval, and maintenance in memory. Hum Brain Mapp 37:3262–3281, 2016. © 2016 Wiley Periodicals, Inc.     

A neural circuit basis for spatial working memory.

The maintenance of a mental image in memory over a time scale of seconds is mediated by the persistent discharges of neurons in a distributed brain network. The representation of the spatial location of a remembered visual stimulus has been studied most extensively and provides the best-understood model of how mnemonic information is encoded in the brain. Neural correlates of spatial working memory are manifested in multiple brain areas, including the prefrontal and parietal association cortices. Spatial working memory ability is severely compromised in schizophrenia, a condition that has been linked to prefrontal cortical malfunction. Recent computational modeling work, in interplay with physiological studies of behaving monkeys, has begun to identify microcircuit properties and neural dynamics that are sufficient to generate memory-related persistent activity in a recurrent network of excitatory and inhibitory neurons during spatial working memory. This review summarizes recent results and discusses issues of current debate. It is argued that understanding collective neural dynamics in a recurrent microcircuit provides a key step in bridging the gap between network memory function and its underlying cellular mechanisms. Progress in this direction will shed fundamental insights into the neural basis of spatial working memory impairment associated with mental disorders.     

Working memory for complex scenes: age differences in frontal and hippocampal activations

Age differences in frontal and hippocampal activations in working memory were investigated during a maintenance and subsequent probe interval in an event-related fMRI design. Younger and older adults either viewed or maintained photographs of real-world scenes (extended visual or maintenance conditions) over a 4-sec interval before responding to a probe fragment from the studied picture. Behavioral accuracy was largely equivalent across age and conditions on the probe task, but underlying neural activations differed. Younger but not older adults showed increased left anterior hippocampal activations in the extended visual compared with the maintenance condition. On the subsequent probe interval, however, older adults showed more left and right inferior frontal activations than younger adults. The increased frontal activations at probe in older adults may have been compensatory for the decreased hippocampal activations during maintenance, but alternatively could have reflected the increased difficulty of the probe task for the older subjects. Thus, we demonstrate qualitatively different engagement of both frontal and hippocampal structures in older adults in a working memory task, despite behavioral equivalence.     

Pharmacological modulation of prefrontal cortical activity during a working memory task in young and older humans: a PET study with physostigmine

OBJECTIVE: Age-associated cholinergic dysfunction may contribute to the cognitive decline observed during aging, including a decline in working memory. The current study was designed to determine how healthy aging influences the neural response to working memory before and during pharmacological potentiation of the cholinergic system. METHOD: In 13 young and 13 older healthy volunteers, regional cerebral blood flow (rCBF) was measured by using [15O]H2O and positron emission tomography across 10 scans that alternated between a working-memory-for-faces task and rest. In all subjects, the first two scans were obtained during intravenous saline infusion. Seven young and eight older subjects then received intravenous infusion of physostigmine, a cholinesterase inhibitor, and the remaining six young and five older subjects continued to receive saline. RESULTS: In the placebo condition, task-specific rCBF increases in prefrontal regions were observed in the right middle and inferior frontal cortices in young subjects and in more anterior and ventral prefrontal regions in older individuals. Physostigmine during the working memory task significantly improved performance in both age groups. The right prefrontal regions that were selectively recruited in each age group during the placebo condition showed significantly lower rCBF during physostigmine administration. CONCLUSIONS: Cholinergic enhancement does not affect structurally defined cortical regions but rather modulates neural activity in functionally defined regions, that is, in task-related prefrontal cortical areas that are selectively and distinctively recruited in young and older subjects.     

Age differences in the frontal lateralization of verbal and spatial working memory revealed by PET

Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline.     

Correlations of striatal dopamine synthesis with default network deactivations during working memory in younger adults

Age‐related deficits have been demonstrated in working memory performance and in the dopamine system thought to support it. We performed positron emission tomography (PET) scans on 12 younger (mean 22.7 years) and 19 older (mean 65.8 years) adults using the radiotracer 6‐[¹⁸F]‐fluoro‐L‐m‐tyrosine (FMT), which measures dopamine synthesis capacity. Subjects also underwent functional magnetic resonance imaging (fMRI) while performing a delayed recognition working memory task. We evaluated age‐related fMRI activity differences and examined how they related to FMT signal variations in dorsal caudate within each age group. In posterior cingulate cortex and precuneus (PCC/Pc), older adults showed diminished fMRI deactivations during memory recognition compared with younger adults. Greater task‐induced deactivation (in younger adults only) was associated both with higher FMT signal and with worse memory performance. Our results suggest that dopamine synthesis helps modulate default network activity in younger adults and that alterations to the dopamine system may contribute to age‐related changes in working memory function. Hum Brain Mapp, 2011. © 2010 Wiley‐Liss, Inc.     

Frontal shift of posterior alpha activity is correlated with cognitive impairment in early Alzheimer's disease: A magnetoencephalography–beamformer study

Background: Induced‐oscillatory activity is considered a key factor for understanding functional processes in the brain. Magnetoencephalography (MEG) can measure oscillatory activity non‐invasively with higher spatial resolution than electroencephalography (EEG). However, MEG has rarely been used to explore functional abnormalities that may represent state markers in patients with Alzheimer's disease (AD). Methods: Thirteen patients with early AD and 14 age‐matched normal controls participated in the present study. Magnetoencephalography activity was acquired during eyes‐open and eyes‐closed states. Alpha event‐related synchronization (ERS) after eye closing was calculated and its cortical sources superimposed on each individual's magnetic resonance imaging (MRI) scan. The resulting functional image was converted into a Talairach‐transformed anatomical brain image and group comparisons were made. We also assessed correlations between cortical ERS sources showing significant between‐group differences in alpha activity and external clinical parameters, especially measures of cognitive function. Results: The averaged alpha ERS after eye closing appeared dominantly in posterior brain regions in both patients with AD and healthy controls. However, there was a significant increase in alpha ERS in frontal regions, maximal over the prefrontal cortex, in patients with AD relative to controls, indicating a frontal shift of the posterior dominant MEG alpha rhythm in AD patients. This frontal ERS source in the alpha band was negatively correlated with Mini‐Mental State Examination scores in the AD patient group. Conclusions: The findings indicate that a frontal shift of alpha ERS elicited by an eyes‐open/eyes‐closed paradigm may be an early brain electromagnetic change in patients with AD, probably representing a physiological state marker of the disease. Furthermore, the results confirm that the beamformer with group comparison analysis is a useful tool with which to explore functional processes in the brain, as indicated by oscillatory activity changes.     

Abnormal distraction and load‐specific connectivity during working memory in cognitively normal Parkinson's disease

Visuospatial working memory impairments are common in Parkinson's disease (PD), yet the underlying neural mechanisms are poorly understood. The present study investigated abnormalities in context‐dependent functional connectivity of working memory hubs in PD. Cognitively normal PD and control participants underwent fMRI while performing a visuospatial working memory task. To identify sources of dysfunction, distraction, and load‐modulated connectivity were disentangled for encoding and retrieval phases of the task. Despite normal working memory performance in PD, two features of abnormal connectivity were observed, one due to a loss in normal context‐related connectivity and another related to upregulated connectivity of hubs for which the controls did not exhibit context‐dependent connectivity. During encoding, striatal‐prefrontal coupling was lost in PD, both during distraction and high memory loads. However, long‐range connectivity of prefrontal, medial temporal and occipital hubs was upregulated in a context‐specific manner. Memory retrieval was characterized by different aberrant connectivity patterns, wherein precuneus connectivity was upregulated during distraction, whereas prefrontal couplings were lost as memory load approached capacity limits. Features of abnormal functional connectivity in PD had pathological and compensatory influences as they correlated with poorer working memory or better visuospatial skills. The results offer new insights into working memory‐related signatures of aberrant cortico–cortical and corticostriatal functional connections, which may portend future declines in different facets of working memory.