α4ß2* Nicotinic Cholinergic Receptor Target Engagement in Parkinson Disease Gait-Balance Disorders.

OBJECTIVE: Attentional deficits following degeneration of brain cholinergic systems contribute to gait-balance deficits in Parkinson disease (PD). As a step toward assessing whether α4ß2* nicotinic acetylcholine receptor (nAChR) stimulation improves gait-balance function, we assessed target engagement of the α4ß2* nAChR partial agonist varenicline. METHODS: Nondemented PD participants with cholinergic deficits were identified with [18 F]fluoroethoxybenzovesamicol positron emission tomography (PET). α4ß2* nAChR occupancy after subacute oral varenicline treatment was measured with [18 F]flubatine PET. With a dose selected from the nAChR occupancy experiment, varenicline effects on gait, balance, and cognition were assessed in a double-masked placebo-controlled crossover study. Primary endpoints were normal pace gait speed and a measure of postural stability. RESULTS: Varenicline doses (0.25mg per day, 0.25mg twice daily [b.i.d.], 0.5mg b.i.d., and 1.0mg b.i.d.) produced 60 to 70% receptor occupancy. We selected 0.5mg orally b.i.d for the crossover study. Thirty-three participants completed the crossover study with excellent tolerability. Varenicline had no significant impact on the postural stability measure and caused slower normal pace gait speed. Varenicline narrowed the difference in normal pace gait speed between dual task and no dual task gait conditions, reduced dual task cost, and improved sustained attention test performance. We obtained identical conclusions in 28 participants with treatment compliance confirmed by plasma varenicline measurements. INTERPRETATION: Varenicline occupied α4ß2* nicotinic acetylcholine receptors, was tolerated well, enhanced attention, and altered gait performance. These results are consistent with target engagement. α4ß2* agonists may be worth further evaluation for mitigation of gait and balance disorders in PD. ANN NEUROL 2021;90:130-142.

Transcranial Direct Current Stimulation Modulates Connectivity of Left Dorsolateral Prefrontal Cortex with Distributed Cortical Networks.

Studies have shown that transcranial direct current stimulation increases neuronal excitability of the targeted region and general connectivity of relevant functional networks. However, relatively little is understood of how the stimulation affects the connectivity relationship of the target with regions across the network structure of the brain. Here, we investigated the effects of transcranial direct current stimulation on the functional connectivity of the targeted region using resting-state fMRI scans of the human brain. Anodal direct current stimulation was applied to the left dorsolateral prefrontal cortex (lDLPFC; cathode on the right bicep), which belongs to the frontoparietal control network (FPCN) and is commonly targeted for neuromodulation of various cognitive functions including short-term memory, long-term memory, and cognitive control. lDLPFC's connectivity characteristics were quantified as graph theory measures, from the resting-state fMRI scans obtained prior to and following the stimulation. Critically, we tested pre- to poststimulation changes of the lDLPFC connectivity metrics following an active versus sham stimulation. We found that the stimulation had two distinct effects on the connectivity of lDLPFC: for Brodmann's area (BA) 9, it increased the functional connectivity between BA 9 and other nodes within the FPCN; for BA 46, net connectivity strength was not altered within FPCN, but connectivity distribution across networks (participation coefficient) was decreased. These findings provide insights that the behavioral changes as the functional consequences of stimulation may come about because of the increased role of lDLPFC in the FPCN.

Neural repetition suppression effects in the human hippocampus.

Neurons in the temporal lobe cortex exhibit reduced responses when a stimulus or a stimulus feature is repeated. This phenomenon, termed "repetition suppression", is the basis for many functional imaging studies that have used Blood Oxygenation Level Dependent (BOLD) activity differences between novel and repeated items as an index of neural selectivity in hippocampal subfields. However, it is not clear how hippocampal neural activity changes across repeated exposure to a stimulus. Here, we used direct intracranial electroencephalography (iEEG) recordings of hippocampal activity to examine whether neural activity in the human hippocampus is modulated across successive repetitions of an item. Time-frequency analyses revealed that high-frequency activity, which is thought to include gamma oscillations and possible correlates of multi-unit activity, declined monotonically across successive presentations of an item. In contrast, low-frequency oscillations in the alpha and beta bands monotonically increased across successive presentations of an object. These results provide support for the assumption that, at least under some circumstances, repetition suppression (as measured by declines in high-frequency activity) can be observed in the hippocampus, and these effects are accompanied by increases in low-frequency oscillations as well.

Compensatory dopaminergic-cholinergic interactions in conflict processing: Evidence from patients with Parkinson's disease.

Executive functions are complex both in the cognitive operations involved and in the neural structures and functions that support those operations. This complexity makes executive function highly vulnerable to the detrimental effects of aging, brain injury, and disease, but may also open paths to compensation. Neural compensation is often used to explain findings of additional or altered patterns of brain activations by older adults or patient populations compared to young adults or healthy controls, especially when associated with relatively preserved performance. Here we test the hypothesis of an alternative form of compensation, between different neuromodulator systems. 135 patients with Parkinson's Disease (PD) completed vesicular monoamine transporter type2 (VMAT2) and acetylcholinesterase PET scanning to assess the integrity of nigrostriatal dopaminergic, thalamic cholinergic, and cortical cholinergic pathways, and a behavioral test (Stroop + task-switching) that puts high demands on conflict processing, an important aspect of executive control. Supporting the compensatory hypothesis, regression models controlling for age and other covariates revealed an interaction between caudate dopamine and cortical cholinergic integrity: Cortical cholinergic integrity was a stronger predictor of conflict processing in patients with relatively low caudate dopaminergic function. These results suggest that although frontostriatal dopaminergic function plays a central role in executive control, cholinergic systems may also make an important contribution. The present results suggest potential pathways for remediation, and that the appropriate interventions for each patient may depend on their particular profile of decline. Furthermore, they help to elucidate the brain systems that underlie executive control, which may be important for understanding other disorders as well as executive function in healthy adults.

The cortical cholinergic system contributes to the top-down control of distraction: Evidence from patients with Parkinson's disease.

Past animal and human studies robustly report that the cholinergic system plays an essential role in both top-down and bottom-up attentional control, as well as other aspects of cognition (see Ballinger et al., 2016 for a recent review). However, current understanding of how two major cholinergic pathways in the human brain (the basal forebrain-cortical pathway, and the brainstem pedunculopontine-thalamic pathway) contribute to specific cognitive functions remains somewhat limited. To address this issue, we examine how individual variation in the integrity of striatal-dopaminergic, thalamic-cholinergic, and cortical-cholinergic pathways (measured using Positron Emission Tomography in patients with Parkinson's disease) was associated with individual variation in the initial goal-directed focus of attention, the ability to sustain attentional performance over time, and the ability to avoid distraction from a highly-salient, but irrelevant, environmental stimulus. Compared to healthy controls, PD patients performed similarly in the precision of attention-dependent judgments of duration, and in sustaining attention over time. However, PD patients' performance was strikingly more impaired by the distractor. More critically, regression analyses indicated that only cortical-cholinergic integrity, not thalamic-cholinergic or striatal-dopaminergic integrity, made a specific contribution to the ability to resist distraction after controlling for the other variables. These results demonstrate that the basal forebrain cortical cholinergic system serves a specific role in executing top-down control to resist external distraction.

The interictal mesial temporal lobe epilepsy network.

OBJECTIVE: Identification of patient-specific epileptogenic networks is critical to designing successful treatment strategies. Multiple noninvasive methods have been used to characterize epileptogenic networks. However, these methods lack the spatiotemporal resolution to allow precise localization of epileptiform activity. We used intracranial recordings, at much higher spatiotemporal resolution, across a cohort of patients with mesial temporal lobe epilepsy (MTLE) to delineate features common to their epileptogenic networks. We used interictal rather than seizure data because interictal spikes occur more frequently, providing us greater power for analyzing variances in the network. METHODS: Intracranial recordings from 10 medically refractory MTLE patients were analyzed. In each patient, hour-long recordings were selected for having frequent interictal discharges and no ictal events. For all possible pairs of electrodes, conditional probability of the occurrence of interictal spikes within a 150-millisecond bin was computed. These probabilities were used to construct a weighted graph between all electrodes, and the node degree was estimated. To assess the relationship of the highly connected regions in this network to the clinically identified seizure network, logistic regression was used to model the regions that were surgically resected using weighted node degree and number of spikes in each channel as factors. Lastly, the conditional spike probability was normalized and averaged across patients to visualize the MTLE network at group level. RESULTS: We generated the first graph of connectivity across a cohort of MTLE patients using interictal activity. The most consistent connections were hippocampus to amygdala, anterior fusiform cortex to hippocampus, and parahippocampal gyrus projections to amygdala. Additionally, the weighted node degree and number of spikes modeled the brain regions identified as seizure networks by clinicians. SIGNIFICANCE: Apart from identifying interictal measures that can model patient-specific epileptogenic networks, we also produce a group map of network connectivity from a cohort of MTLE patients.

Thalamic cholinergic innervation makes a specific bottom-up contribution to signal detection: Evidence from Parkinson's disease patients with defined cholinergic losses.

Successful behavior depends on the ability to detect and respond to relevant cues, especially under challenging conditions. This essential component of attention has been hypothesized to be mediated by multiple neuromodulator systems, but the contributions of individual systems (e.g., cholinergic, dopaminergic) have remained unclear. The present study addresses this issue by leveraging individual variation in regionally-specific cholinergic denervation in Parkinson's disease (PD) patients, while controlling for variation in dopaminergic denervation. Patients whose dopaminergic and cholinergic nerve terminal integrity had been previously assessed using Positron Emission Tomography (Bohnen et al., 2012) and controls were tested in a signal detection task that manipulates attentional-perceptual challenge and has been used extensively in both rodents and humans to investigate the cholinergic system's role in responding to such challenges (Demeter et al., 2008; McGaughy and Sarter, 1995; see Hasselmo and Sarter 2011 for review). In simple correlation analyses, measures of midbrain dopaminergic, and both cortical and thalamic cholinergic innervation all predicted preserved signal detection under challenge. However, regression analyses also controlling for age, disease severity, and other variables showed that the only significant independent neurotransmitter-related predictor over and above the other variables in the model was thalamic cholinergic integrity. Furthermore, thalamic cholinergic innervation exclusively predicted hits, not correct rejections, indicating a specific contribution to bottom-up salience processing. These results help define regionally-specific contributions of cholinergic function to different aspects of attention and behavior.

A network approach for modulating memory processes via direct and indirect brain stimulation: Toward a causal approach for the neural basis of memory.

Electrical stimulation of the brain is a unique tool to perturb endogenous neural signals, allowing us to evaluate the necessity of given neural processes to cognitive processing. An important issue, gaining increasing interest in the literature, is whether and how stimulation can be employed to selectively improve or disrupt declarative memory processes. Here, we provide a comprehensive review of both invasive and non-invasive stimulation studies aimed at modulating memory performance. The majority of past studies suggest that invasive stimulation of the hippocampus impairs memory performance; similarly, most non-invasive studies show that disrupting frontal or parietal regions also impairs memory performance, suggesting that these regions also play necessary roles in declarative memory. On the other hand, a handful of both invasive and non-invasive studies have also suggested modest improvements in memory performance following stimulation. These studies typically target brain regions connected to the hippocampus or other memory "hubs," which may affect endogenous activity in connected areas like the hippocampus, suggesting that to augment declarative memory, altering the broader endogenous memory network activity is critical. Together, studies reporting memory improvements/impairments are consistent with the idea that a network of distinct brain "hubs" may be crucial for successful memory encoding and retrieval rather than a single primary hub such as the hippocampus. Thus, it is important to consider neurostimulation from the network perspective, rather than from a purely localizationalist viewpoint. We conclude by proposing a novel approach to neurostimulation for declarative memory modulation that aims to facilitate interactions between multiple brain "nodes" underlying memory rather than considering individual brain regions in isolation.

Sensitivity to and Control of Distraction: Distractor-Entrained Oscillation and Frontoparietal EEG Gamma Synchronization.

While recent advancements have been made towards a better understanding of the involvement of the prefrontal cortex (PFC) in the context of cognitive control, the exact mechanism is still not fully understood. Successful behavior requires the correct detection of goal-relevant cues and resisting irrelevant distractions. Frontal parietal networks have been implicated as important for maintaining cognitive control in the face of distraction. The present study investigated the role of gamma-band power in distraction resistance and frontoparietal networks, as its increase is linked to cholinergic activity. We examined changes in gamma activity and their relationship to frontoparietal top-down modulation for distractor challenges and to bottom-up distractor processing. Healthy young adults were tested using a modified version of the distractor condition sustained attention task (dSAT) while wearing an EEG. The modified distractor was designed so that oscillatory activities could be entrained to it, and the strength of entrainment was used to assess the degree of distraction. Increased top-down control during the distractor challenge increased gamma power in the left parietal regions rather than the right prefrontal regions predicted from rodent studies. Specifically, left parietal gamma power increased in response to distraction where the amount of this increase was negatively correlated with the neural activity reflecting bottom-up distractor processing in the visual area. Variability in gamma power in right prefrontal regions was associated with increased response time variability during distraction. This may suggest that the right prefrontal region may contribute to the signaling needed for top-down control rather than its implementation.

Individual differences in behavioral and electrophysiological signatures of familiarity- and recollection-based recognition memory.

Our everyday memories can vary in terms of accuracy and phenomenology. According to one theoretical account, these differences hinge on whether the memories contain information about both an item itself as well as associated details (remember) versus those that are devoid of these associated contextual details (familiar). This distinction has been supported by computational modeling of behavior, studies in patients, and neuroimaging work including differences both in electrophysiological and functional magnetic resonance imaging. At present, however, little evidence has emerged to suggest that neurophysiological measures track individual differences in estimates of recollection and familiarity. Here, we conducted electrophysiological recordings of brain activity during a recognition memory task designed to differentiate between behavioral indices of recollection and familiarity. Non-parametric cluster-based permutation analyses revealed associations between electrophysiological signatures of familiarity and recollection with their respective behavioral estimates. These results support the idea that recollection and familiarity are distinct phenomena and is the first, to our knowledge, to identify distinct electrophysiological signatures that track individual differences in these processes.

Intensity-Dependent Changes in Quantified Resting Cerebral Perfusion With Multiple Sessions of Transcranial DC Stimulation.

Transcranial direct current stimulation (tDCS) to the left prefrontal cortex has been shown to produce broad behavioral effects including enhanced learning and vigilance. Still, the neural mechanisms underlying such effects are not fully understood. Furthermore, the neural underpinnings of repeated stimulation remain understudied. In this work, we evaluated the effects of the repetition and intensity of tDCS on cerebral perfusion [cerebral blood flow (CBF)]. A cohort of 47 subjects was randomly assigned to one of the three groups. tDCS of 1- or 2-mA was applied to the left prefrontal cortex on three consecutive days, and resting CBF was quantified before and after stimulation using the arterial spin labeling MRI and then compared with a group that received sham stimulation. A widespread decreased CBF was found in a group receiving sham stimulation across the three post-stimulation measures when compared with baseline. In contrast, only slight decreases were observed in the group receiving 2-mA stimulation in the second and third post-stimulation measurements, but more prominent increased CBF was observed across several brain regions including the locus coeruleus (LC). The LC is an integral region in the production of norepinephrine and the noradrenergic system, and an increased norepinephrine/noradrenergic activity could explain the various behavioral findings from the anodal prefrontal tDCS. A decreased CBF was observed in the 1-mA group across the first two post-stimulation measurements, similar to the sham group. This decreased CBF was apparent in only a few small clusters in the third post-stimulation scan but was accompanied by an increased CBF, indicating that the neural effects of stimulation may persist for at least 24 h and that the repeated stimulation may produce cumulative effects.

The hippocampus constructs narrative memories across distant events.

Life's events are scattered throughout time, yet we often recall different events in the context of an integrated narrative. Prior research suggests that the hippocampus, which supports memory for past events, can support the integration of overlapping associations or separate events in memory. However, the conditions that lead to hippocampus-dependent memory integration are unclear. We used functional brain imaging to test whether the opportunity to form a larger narrative (narrative coherence) drives hippocampal memory integration. During encoding of fictional stories, patterns of hippocampal activity, including activity at boundaries between events, were more similar between distant events that formed one coherent narrative, compared with overlapping events taken from unrelated narratives. One day later, the hippocampus preferentially supported detailed recall of coherent narrative events, through reinstatement of hippocampal activity patterns from encoding. These findings demonstrate a key function of the hippocampus: the integration of events into a narrative structure for memory.

Impact of oscillatory tDCS targeting left prefrontal cortex on source memory retrieval.

Research on transcranial direct current stimulation (tDCS) has grown rapidly, but there is controversy regarding whether and how tDCS could impact memory performance. We report a study that addressed this question by examining the effects of oscillatory tDCS (otDCS) on subsequent episodic memory performance and concomitant recordings of neural oscillations. Neural oscillations in the theta band (4-7 Hz) have been shown to be important for episodic memory and especially for source memory retrieval. Here, we tested the effects of anodal otDCS at theta (5.5 Hz) over the left DLPFC on theta oscillations and memory performance. In two sessions, participants completed an item and source recognition paradigm with word stimuli. Between study and test, participants received otDCS in one session and sham stimulation in the other. Surprisingly, behavioral results showed that, relative to the sham stimulation, otDCS impaired source memory performance. Analyses of EEG data during memory retrieval revealed that otDCS changed pre-stimulus theta power and in particular reduced the specificity of theta activity during source memory retrieval. Our results suggest that non-invasive brain stimulation can impact memory and oscillatory activity in counterintuitive ways, and that direct neural activity measures can facilitate meaningful interpretation of behavioral effects of stimulation.

Network-based brain stimulation selectively impairs spatial retrieval.

BACKGROUND: Direct brain stimulation via electrodes implanted for intracranial electroencephalography (iEEG) permits the modulation of endogenous electrical signals with significantly greater spatial and temporal specificity than non-invasive approaches. It also allows for the stimulation of deep brain structures important to memory, such as the hippocampus, that are difficult, if not impossible, to target non-invasively. Direct stimulation studies of these deep memory structures, though, have produced mixed results, with some reporting improvement, some impairment, and others, no consistent changes. OBJECTIVE/HYPOTHESIS: We hypothesize that to modulate cognitive function using brain stimulation, it is essential to modulate connected nodes comprising a network, rather than just alter local activity. METHODS: iEEG data collected while patients performed a spatiotemporal memory retrieval task were used to map frequency-specific, coherent oscillatory activity between different brain regions associated with successful memory retrieval. We used these to identify two target nodes that exhibited selectively stronger coupling for spatial vs. temporal retrieval. In a subsequent session, electrical stimulation - theta-bursts with a fixed phase-lag (0° or 180°) - was applied to the two target regions while patients performed spatiotemporal retrieval. RESULTS: Stimulation selectively impaired spatial retrieval while not affecting temporal retrieval, and this selective impairment was associated with theta decoupling of the spatial retrieval network. CONCLUSION: These findings suggest that stimulating tightly connected nodes in a functional network at the appropriate phase-lag may effectively modulate the network function, and while in this case it impaired memory processes, it sets a foundation for further network-based perturbation studies.

Neural congruency effects in the multi-source interference task vanish in healthy youth after controlling for conditional differences in mean RT.

According to the conflict monitoring model of cognitive control, reaction time (RT) in distracter interference tasks (e.g., the Stroop task) is a more precise index of response conflict than stimulus congruency (incongruent vs. congruent). The model therefore predicts that RT should be a reliable predictor of activity in regions of the posterior medial frontal cortex (pMFC) that are posited to detect response conflict. In particular, pMFC activity should be (a) greater in slow-RT than in fast-RT trials within a given task condition (e.g., congruent) and (b) equivalent in RT-matched trials from different conditions (i.e., congruent and incongruent trials). Both of these effects have been observed in functional magnetic resonance imaging (MRI) studies of adults. However, neither effect was observed in a recent study of healthy youth, suggesting that (a) the model does not accurately describe the relationship between RT and pMFC activity in this population or (b) the recent study was characterized by high variability due to a relatively small sample size. To distinguish between these possibilities, we asked a relatively large group of healthy youth (n = 28) to perform a distracter interference task - the multi-source interference task (MSIT) - while we recorded their brain activity with functional MRI. In this relatively large sample, both of the model's predictions were confirmed. We conclude that the model accurately describes the relationship between pMFC activity and RT in healthy youth, but that additional research is needed to determine whether processes unrelated to response conflict contribute to this relationship.

Conditional Differences in Mean Reaction Time Explain Effects of Response Congruency, but not Accuracy, on Posterior Medial Frontal Cortex Activity.

According to the conflict-monitoring model of cognitive control, the posterior medial frontal cortex (pMFC) plays an important role in detecting conflict between competing motor responses. Consistent with this view, pMFC activity is greater in high-conflict trials (e.g., incongruent trials and errors) than in low-conflict trials (e.g., congruent trials and correct responses) of distractor interference tasks. However, in both low- and high-conflict trials, pMFC activity increases linearly with reaction time (RT). Thus, heightened pMFC activity in high-conflict trials may simply reflect the fact that mean RT is longer in high-conflict than in low-conflict trials. To investigate this hypothesis, we reanalyzed data from a previously published fMRI study in which participants performed an event-related version of the multi-source interference task. Critically, after controlling for conditional differences in mean RT, effects of response congruency on pMFC activity were eliminated; in contrast, effects of response accuracy on pMFC activity remained robust. These findings indicate that effects of response congruency on pMFC activity may index any of several processes whose recruitment increases with time on task (e.g., sustained attention). However, effects of response accuracy reflect processes unique to error trials. We conclude that effects of response accuracy on pMFC activity provide stronger support for the conflict-monitoring model than effects of response congruency.