Flexible behavior requires gating mechanisms that encode only task-relevant information in working memory. Extant literature supports a theoretical division of labor whereby lateral frontoparietal interactions underlie information maintenance and the striatum enacts the gate. Here, we reveal neocortical gating mechanisms in intracranial EEG patients by identifying rapid, within-trial changes in regional and inter-regional activities that predict subsequent behavioral outputs. Results first demonstrate information accumulation mechanisms that extend prior fMRI (i.e., regional high-frequency activity) and EEG evidence (inter-regional theta synchrony) of distributed neocortical networks in working memory. Second, results demonstrate that rapid changes in theta synchrony, reflected in changing patterns of default mode network connectivity, support filtering. Graph theoretical analyses further linked filtering in task-relevant information and filtering out irrelevant information to dorsal and ventral attention networks, respectively. Results establish a rapid neocortical theta network mechanism for flexible information encoding, a role previously attributed to the striatum.

Precision neuromodulation of central brain circuits is a promising emerging therapeutic modality for a variety of neuropsychiatric disorders. Reliably identifying in whom, where, and in what context to provide brain stimulation for optimal pain relief are fundamental challenges limiting the widespread implementation of central neuromodulation treatments for chronic pain. Current approaches to brain stimulation target empirically derived regions of interest to the disorder or targets with strong connections to these regions. However, complex, multidimensional experiences like chronic pain are more closely linked to patterns of coordinated activity across distributed large-scale functional networks. Recent advances in precision network neuroscience indicate that these networks are highly variable in their neuroanatomical organization across individuals. Here we review accumulating evidence that variable central representations of pain will likely pose a major barrier to implementation of population-derived analgesic brain stimulation targets. We propose network-level estimates as a more valid, robust, and reliable way to stratify personalized candidate regions. Finally, we review key background, methods, and implications for developing network topology-informed brain stimulation targets for chronic pain.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [F]Fluoro-m-tyrosine ([F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and β-amyloid (Aβ) pathology using cross-sectional [F]Flortaucipir and [C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

The role of the lateral prefrontal cortex (lPFC) in working memory (WM) is debated. Non-human primate (NHP) electrophysiology shows that the lPFC stores WM representations, but human neuroimaging suggests that the lPFC controls WM content in sensory cortices. These accounts are confounded by differences in task training and stimulus exposure. We tested whether long-term training alters lPFC function by densely sampling WM activity using functional MRI. Over 3 months, participants trained on both a WM and serial reaction time (SRT) task, wherein fractal stimuli were embedded within sequences. WM performance improved for trained (but not novel) fractals and, neurally, delay activity increased in distributed lPFC voxels across learning. Item-level WM representations became detectable within lPFC patterns, and lPFC activity reflected sequence relationships from the SRT task. These findings demonstrate that human lPFC develops stimulus-selective responses with learning, and WM representations are shaped by long-term experience, which could reconcile competing accounts of WM functioning.