Summary Episodic memory is thought to critically depend on interaction of the hippocampus with distributed brain regions [1–3]. Specific contributions of distinct networks have been hypothesized, with the hippocampal posterior-medial (HPM) network implicated in recollection of highly precise contextual and spatial information [3–6]. Current evidence for HPM specialization is mostly indirect, derived from correlative measures such as neural activity recordings. Here, we tested the causal role of HPM in recollection using network-targeted noninvasive brain stimulation in humans, which has previously been shown to increase functional connectivity within the HPM network [7]. Effects of multiple-day electromagnetic stimulation were assessed using an object-location memory task that segregated recollection precision from general recollection success. HPM network-targeted stimulation produced lasting (~24 h) enhancement of recollection precision, without effects on general success. Canonical neural correlates of recollection [8–10] were also modulated by stimulation. Late-positive evoked potential amplitude and theta-alpha oscillatory power were reduced, suggesting that stimulation can improve memory through enhanced reactivation of detailed visuospatial information at retrieval. The HPM network was thus specifically implicated in processing of fine-grained memory detail, supporting functional specialization of hippocampal-cortical networks. These findings demonstrate that brain networks can be causally linked to distinct and specific neurocognitive functions and suggest mechanisms for long-lasting changes in memory due to network-targeted stimulation.

The molecular chaperone Hsp33 in Escherichia coli responds to oxidative stress conditions with the rapid activation of its chaperone function. On its activation pathway, Hsp33 progresses through three major conformations, starting as a reduced, zinc-bound inactive monomer, proceeding through an oxidized zinc-free monomer, and ending as a fully active oxidized dimer. While it is known that Hsp33 senses oxidative stress through its C-terminal four-cysteine zinc center, the nature of the conformational changes in Hsp33 that must take place to accommodate this activation process is largely unknown. To investigate these conformational rearrangements, we constructed constitutively monomeric Hsp33 variants as well as fragments consisting of the redox regulatory C-terminal domain of Hsp33. These proteins were studied by a combination of biochemical and NMR spectroscopic techniques. We found that in the reduced, monomeric conformation, zinc binding stabilizes the C terminus of Hsp33 in a highly compact, ␣-helical structure. This appears to conceal both the substrate-binding site as well as the dimerization interface. Zinc release without formation of the two native disulfide bonds causes the partial unfolding of the C terminus of Hsp33. This is sufficient to unmask the substrate-binding site, but not the dimerization interface, rendering reduced zinc-free Hsp33 partially active yet monomeric. Critical for the dimerization is disulfide bond formation, which causes the further unfolding of the C terminus of Hsp3 and allows the association of two oxidized Hsp33 monomers. This then leads to the formation of active Hsp33 dimers, which are capable of protecting cells against the severe consequences of oxidative heat stress.

Targeted noninvasive stimulation selectively increases activity of the human hippocampal network during memory formation.

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Episodic memory is thought to rely on interactions of the hippocampus with other regions of the distributed hippocampal-cortical network (HCN) via interregional activity synchrony in the theta frequency band. We sought to causally test this hypothesis using network-targeted transcranial magnetic stimulation. Healthy human participants completed four experimental sessions, each involving a different stimulation pattern delivered to the same individualized parietal cortex location of the HCN for all sessions. There were three active stimulation conditions, including continuous theta-burst stimulation, intermittent theta-burst stimulation, and beta-frequency (20-Hz) repetitive stimulation, and one sham condition. Resting-state fMRI and episodic memory testing were used to assess the impact of stimulation on hippocampal fMRI connectivity related to retrieval success. We hypothesized that theta-burst stimulation conditions would most strongly influence hippocampal-HCN fMRI connectivity and retrieval, given the hypothesized relevance of theta-band activity for HCN memory function. Continuous theta-burst stimulation improved item retrieval success relative to sham and relative to beta-frequency stimulation, whereas intermittent theta-burst stimulation led to numerical but nonsignificant item retrieval improvement. Mean hippocampal fMRI connectivity did not vary for any stimulation conditions, whereas individual differences in retrieval improvements due to continuous theta-burst stimulation were associated with corresponding increases in fMRI connectivity between the hippocampus and other HCN locations. No such memory-related connectivity effects were identified for the other stimulation conditions, indicating that only continuous theta-burst stimulation affected memory-related hippocampal-HCN connectivity. Furthermore, these effects were specific to the targeted HCN, with no significant memory-related fMRI connectivity effects for two distinct control brain networks. These findings support a causal role for fMRI connectivity of the hippocampus with the HCN in episodic memory retrieval and indicate that contributions of this network to retrieval are particularly sensitive to continuous theta-burst noninvasive stimulation.

Successful episodic recollection can vary in the precision of the information recalled. The hypothesis that recollection precision requires functional neuroanatomical contributions distinct from those required for recollection success remains controversial. Some findings in individuals with hippocampal lesions have indicated that precision is dependent on the hippocampus. However, other neuroimaging and lesion studies have implicated regions outside of the mesial temporal lobe (MTL) in precision, such as parietal cortex. To further elucidate distinctions of recollection precision versus success, we examined whether they were differentially sensitive to aging and to unilateral MTL lesions. Precision and success were measured using a novel task that required memory for item-location associations across different spatial contexts. We found impairments in recollection precision, but not success, in older adults (59-80 years) relative to younger adults (18-33 years). Recollection precision was also selectively impaired in individuals with unilateral MTL resections made to treat refractory epilepsy. Moreover, recollection precision was significantly worse when resections included the hippocampus compared to when only non-hippocampal MTL tissue was resected. These findings suggest that the MTL is critically involved in the high-resolution binding required to support spatial recollection precision, and thus provide evidence for functional neuroanatomical differences between recollection success and precision.

ObjectiveTo test whether targeting hippocampal-cortical brain networks with high-frequency transcranial magnetic stimulation in older adults influences behavioral and neural measures characteristic of age-related memory impairment.MethodsFifteen adults aged 64 to 80 years (mean = 72 years) completed a single-blind, sham-controlled experiment. Stimulation targets in parietal cortex were determined based on fMRI connectivity with the hippocampus. Recollection and recognition memory were assessed after 5 consecutive daily sessions of full-intensity stimulation vs low-intensity sham stimulation using a within-subjects crossover design. Neural correlates of recollection and recognition memory formation were obtained via fMRI, measured within the targeted hippocampal-cortical network vs a control frontal-parietal network. These outcomes were measured approximately 24 hours after the final stimulation session.ResultsRecollection was specifically impaired in older adults compared to a young-adult control sample at baseline. Relative to sham, stimulation improved recollection to a greater extent than recognition. Stimulation increased recollection fMRI signals throughout the hippocampal-cortical network, including at the targeted location of the hippocampus. Effects of stimulation on fMRI recollection signals were greater than those for recognition and were greater in the targeted network compared to the control network.ConclusionsAge-related recollection impairments were causally related to hippocampal-cortical network function in older adults. Stimulation selectively modified neural and behavioral hallmarks of age-related memory impairment, indicating effective engagement of memory intervention targets in older adults.

OBJECTIVESudden unexpected death in epilepsy (SUDEP) is the leading cause of death for patients with refractory epilepsy, and there is increasing evidence for a centrally mediated respiratory depression as a pathophysiological mechanism. The brain regions responsible for a seizure’s inducing respiratory depression are unclear—the respiratory nuclei in the brainstem are thought to be involved, but involvement of forebrain structures is not yet understood. The aim of this study was to analyze intracranial EEGs in combination with the results of respiratory monitoring to investigate the relationship between seizure spread to specific mesial temporal brain regions and the onset of respiratory dysfunction and apnea.METHODSThe authors reviewed all invasive electroencephalographic studies performed at Northwestern Memorial Hospital (Chicago) since 2010 to identify those cases in which 1) multiple mesial temporal electrodes (amygdala and hippocampal) were placed, 2) seizures were captured, and 3) patients’ respiration was monitored. They identified 8 investigations meeting these criteria in patients with temporal lobe epilepsy, and these investigations yielded data on a total of 22 seizures for analysis.RESULTSThe onset of ictal apnea associated with each seizure was highly correlated with seizure spread to the amygdala. Onset of apnea occurred 2.7 ± 0.4 (mean ± SEM) seconds after the spread of the seizure to the amygdala, which was significantly earlier than after spread to the hippocampus (10.2 ± 0.7 seconds; p < 0.01).CONCLUSIONSThe findings suggest that activation of amygdalar networks is correlated with central apnea during seizures. This study builds on the authors’ prior work that demonstrates a role for the amygdala in voluntary respiratory control and suggests a further role in dysfunctional breathing states seen during seizures, with implications for SUDEP pathophysiology.