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Protein kinase C (PKC) functions are essential for synaptic plasticity, learning, and memory. However, the roles of specific members of the PKC family in synaptic function, learning, and memory are poorly understood. Here, we investigated the role of individual PKC homologs for synaptic plasticity in Caenorhabditis elegans and found a differential role for pkc-2 and tpa-1, but not pkc-1 and pkc-3 in associative olfactory learning and memory. More specifically we show that PKC-2 is essential for associative learning and TPA-1 for short-term associative memory (STAM). Using endogenous labeling and cell-specific rescues, we show that TPA-1 and PKC-2 are required in AVA for their functions. Previous studies demonstrated that olfactory learning and memory in C. elegans are tied to proper synaptic content and trafficking of AMPA-type ionotropic glutamate receptor homolog GLR-1 in the AVA command interneurons. Therefore, we quantified synaptic content, transport, and delivery of GLR-1 in AVA and showed that loss of pkc-2 and tpa-1 leads to decreased transport and delivery but only a subtle decrease in GLR-1 levels at synapses. AVA-specific expression of both PKC-2 and TPA-1 rescued these defects. Finally, genetic epistasis showed that PKC-2 and TPA-1 likely act in the same pathway to control GLR-1 transport and delivery, while regulating different aspects of olfactory learning and STAM. Thus, our data tie together cell-specific functions of 2 PKCs to neuronal and behavioral outcomes in C. elegans, enabling comparative approaches to understand the evolutionarily conserved role of PKC in synaptic plasticity, learning, and memory.
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Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animales , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Aprendizaje , Proteína Quinasa C/metabolismo , Receptores AMPA/metabolismo , Sinapsis/metabolismoRESUMEN
Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution fMRI, and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure (in both sexes). Behaviorally, hydrocortisone promoted the encoding of subjectively arousing, positive associative memories. Neurally, hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional associations. Cortisol also modified the relationship between hippocampal representations and associative memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional associative memory enhancements under cortisol.SIGNIFICANCE STATEMENT Our daily lives are filled with stressful events, which powerfully shape the way we form episodic memories. For example, stress and stress-related hormones can enhance our memory for emotional events. However, the mechanisms underlying these memory benefits are unclear. In the current study, we combined functional neuroimaging, behavioral tests of memory, and double-blind, placebo-controlled hydrocortisone administration to uncover the effects of the stress-related hormone cortisol on the function of the human hippocampus, a brain region important for episodic memory. We identified novel ways in which cortisol can enhance hippocampal function to promote emotional memories, highlighting the adaptive role of cortisol in shaping memory formation.
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Hidrocortisona , Memoria Episódica , Masculino , Femenino , Humanos , Hidrocortisona/farmacología , Encéfalo , Hipocampo , Emociones , Imagen por Resonancia Magnética/métodosRESUMEN
Our ability to navigate in a new environment depends on learning new locations. Mental representations of locations are quickly accessible during navigation and allow us to know where we are regardless of our current viewpoint. Recent functional magnetic resonance imaging (fMRI) research using pattern classification has shown that these location-based representations emerge in the retrosplenial cortex and parahippocampal gyrus, regions theorized to be critically involved in spatial navigation. However, little is currently known about the oscillatory dynamics that support the formation of location-based representations. We used magnetoencephalogram (MEG) recordings to investigate region-specific oscillatory activity in a task where participants could form location-based representations. Participants viewed videos showing that two perceptually distinct scenes (180° apart) belonged to the same location. This "overlap" video allowed participants to bind the two distinct scenes together into a more coherent location-based representation. Participants also viewed control "non-overlap" videos where two distinct scenes from two different locations were shown, where no location-based representation could be formed. In a post-video behavioral task, participants successfully matched the two viewpoints shown in the overlap videos, but not the non-overlap videos, indicating they successfully learned the locations in the overlap condition. Comparing oscillatory activity between the overlap and non-overlap videos, we found greater theta and alpha/beta power during the overlap relative to non-overlap videos, specifically at time-points when we expected scene integration to occur. These oscillations localized to regions in the medial parietal cortex (precuneus and retrosplenial cortex) and the medial temporal lobe, including the hippocampus. Therefore, we find that theta and alpha/beta oscillations in the hippocampus and medial parietal cortex are likely involved in the formation of location-based representations.
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Ritmo alfa , Hipocampo , Magnetoencefalografía , Lóbulo Parietal , Ritmo Teta , Humanos , Lóbulo Parietal/fisiología , Lóbulo Parietal/diagnóstico por imagen , Magnetoencefalografía/métodos , Masculino , Ritmo Teta/fisiología , Hipocampo/fisiología , Hipocampo/diagnóstico por imagen , Femenino , Adulto Joven , Adulto , Ritmo alfa/fisiología , Estimulación Luminosa/métodos , Percepción Espacial/fisiología , Navegación Espacial/fisiologíaRESUMEN
Associative memory refers to the ability to form and remember associations between individual pieces of information rather than memory for a single object or word. Encoding associations in memory tends to be a more difficult task than item (only) encoding, because associative memory requires encoding multiple items as well as the specific links amongst the items. Accordingly, researchers have worked to identify interventions and strategies to reduce the effort and neural resources required for successful associative memory processing. Unitization is one such strategy that has traditionally been defined as the process by which two or more discrete items are processed, or encoded, such that they are perceived as a single ensemble. The current review explores the neural research on unitization while considering the behavioral benefits that accompany the process.
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Aprendizaje por Asociación , Encéfalo , Humanos , Encéfalo/fisiología , Aprendizaje por Asociación/fisiología , Memoria/fisiología , AnimalesRESUMEN
Associative learning and memory are fundamental behavioral processes through which organisms adapt to complex environments. Associative memory involves long-lasting changes in synaptic plasticity. Dendritic spines are tiny protrusions from the dendritic shaft of principal neurons, providing the structural basis for synaptic plasticity and brain networks in response to external stimuli. Mounting evidence indicates that dendritic spine dynamics are crucial in different associative memory phases, including acquisition, consolidation, and reconsolidation. Causally bridging dendritic spine dynamics and associative memory is still limited by the suitable tools to measure and control spine dynamics in vivo under behaviorally relevant conditions. Here, we review data providing evidence for the remodeling of dendritic spines during associative memory processing and outline open questions.
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Espinas Dendríticas , Plasticidad Neuronal , Plasticidad Neuronal/fisiología , Encéfalo/fisiología , Memoria/fisiología , Neuronas , SinapsisRESUMEN
Under what conditions can prefrontal cortex direct the composition of brain states, to generate coherent streams of thoughts? Using a simplified Potts model of cortical dynamics, crudely differentiated into two halves, we show that once activity levels are regulated, so as to disambiguate a single temporal sequence, whether the contents of the sequence are mainly determined by the frontal or by the posterior half, or by neither, depends on statistical parameters that describe its microcircuits. The frontal cortex tends to lead if it has more local attractors, longer lasting and stronger ones, in order of increasing importance. Its guidance is particularly effective to the extent that posterior cortices do not tend to transition from state to state on their own. The result may be related to prefrontal cortex enforcing its temporally-oriented schemata driving coherent sequences of brain states, unlike the atemporal "context" contributed by the hippocampus. Modelling a mild prefrontal (vs. posterior) lesion offers an account of mind-wandering and event construction deficits observed in prefrontal patients.
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Corteza Prefrontal , Pensamiento , Corteza Prefrontal/fisiología , Humanos , Pensamiento/fisiología , Modelos Neurológicos , Factores de TiempoRESUMEN
It is proposed that older adults have difficulties to bind item and context and to recruit deep, elaborative processing during encoding. Senescent changes in the oscillatory foundations of these processes are currently unclear. We recorded electroencephalography during item-context memory formation in younger (n = 57) and older (n = 55) adults. At test, we assessed memory for the items and the item-context pairs and examined encoding-related activity based on how much information was recovered at retrieval (miss < item-only < pair). Item memory was comparable between age groups while pair memory was reduced in the older adults. Theta synchronization and alpha/beta desynchronization increased linearly with the amount of information available. Single-trial theta power could not predict subsequent item memory, but predicted pair memory in an age-invariant manner, in line with a mechanism supporting associative memory. In contrast, single-trial alpha/beta power predicted both item and pair memory, in line with a mechanism reflecting the depth of information processing, and predicted pair memory less well in the older than the younger adults. Thus, theta and alpha/beta oscillations contribute differently in shaping the contents of memories and reduced processing capacity contributes to episodic memory decline in older age.
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Electroencefalografía , Memoria Episódica , CogniciónRESUMEN
Hippocampal theta oscillations have been implicated in associative memory in humans. However, findings from electrophysiological studies using scalp electroencephalography or magnetoencephalography, and those using intracranial electroencephalography are mixed. Here we asked 10 pre-surgical epilepsy patients undergoing intracranial electroencephalography recording, along with 21 participants undergoing magnetoencephalography recordings, to perform an associative memory task, and examined whether hippocampal theta activity during encoding was predictive of subsequent associative memory performance. Across the intracranial electroencephalography and magnetoencephalography studies, we observed that theta power in the hippocampus increased during encoding, and that this increase differed as a function of subsequent memory, with greater theta activity for pairs that were successfully retrieved in their entirety compared with those that were not remembered. This helps to clarify the role of theta oscillations in associative memory formation in humans, and further, demonstrates that findings in epilepsy patients undergoing intracranial electroencephalography recordings can be extended to healthy participants undergoing magnetoencephalography recordings.
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Epilepsia , Ritmo Teta , Humanos , Ritmo Teta/fisiología , Hipocampo/fisiología , Electroencefalografía , Recuerdo Mental/fisiología , Epilepsia/cirugíaRESUMEN
Both, the hippocampal formation and the neocortex are contributing to declarative memory, but their functional specialization remains unclear. We investigated the differential contribution of both memory systems during free recall of word lists. In total, 21 women and 17 men studied the same list but with the help of different encoding associations. Participants associated the words either sequentially with the previous word on the list, with spatial locations on a well-known path, or with unique autobiographical events. After intensive rehearsal, subjects recalled the words during functional magnetic resonance imaging (fMRI). Common activity to all three types of encoding associations was identified in the posterior parietal cortex, in particular in the precuneus. Additionally, when associating spatial or autobiographical material, retrosplenial cortex activity was elicited during word list recall, while hippocampal activity emerged only for autobiographically associated words. These findings support a general, critical function of the precuneus in episodic memory storage and retrieval. The encoding-retrieval repetitions during learning seem to have accelerated hippocampus-independence and lead to direct neocortical integration in the sequentially associated and spatially associated word list tasks. During recall of words associated with autobiographical memories, the hippocampus might add spatiotemporal information supporting detailed scenic and contextual memories.
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Memoria Episódica , Neocórtex , Masculino , Humanos , Femenino , Lóbulo Parietal/diagnóstico por imagen , Recuerdo Mental , Hipocampo/diagnóstico por imagen , Neocórtex/diagnóstico por imagen , Imagen por Resonancia Magnética , Mapeo EncefálicoRESUMEN
Whereas previous research has concentrated on the emergence of episodic memory during the early years, fewer investigations have explored the details of this development through middle and late childhood. Considerable variation in task demands and testing methodologies have rendered the trajectory of episodic memory during this period unclear, particularly with regard to which elements are in a state of change at which time. This study separately assessed memory for item, location, and temporal order, as well as integrated what-where-when (WWW) information using a WWW memory test (the Treasure Hunt task), with 84 children aged 6 to 12 years. Two versions of the task were used, varying in the degree of retrieval support while keeping encoding constant. Results show that episodic memory continued to develop across this period, with individual item, spatial, temporal, and WWW memory all improving relatively linearly with age. These improvements were underpinned by both the associative binding and strategic control processes. These findings suggest that it is not any one element of episodic memory that is driving development during this period but that all aspects are continuing to mature in parallel.
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Memoria Episódica , Humanos , Niño , Recuerdo MentalRESUMEN
Episodic memory comprises memory for individual information units (item memory) and for the connections among them (associative memory). In two experiments using an object pair learning task, we examined the effect of visual stimulus complexity on memory encoding and retrieval mechanisms and on item and associative memory performance. Subjects encoded pairs of black monochrome object images (low complexity, LC condition) or color photographs of objects (high complexity, HC condition) via interactive imagery, and subsequently item and associative recognition were tested. In Experiment 1, event-related potentials (ERPs) revealed an enhanced frontal N2 during encoding and an enhanced late posterior negativity (LPN) during item recognition in the HC condition, suggesting that memory traces containing visually more complex objects elicited a stronger effort in reconstructing the past episode. Item memory was consistently superior in the HC compared to the LC condition. Associative memory was either statistically unaffected by complexity (Experiment 1) or improved (Experiment 2) in the HC condition, speaking against a tradeoff between resources allocated to item versus associative memory, and hence contradicting results of some prior studies. In Experiment 2, in both young and older adults, both item and associative memory benefitted from stimulus complexity, such that the magnitude of the age-related associative deficit was not influenced by stimulus complexity. Together, these results suggest that if familiar objects are presented in a form that exhibits a higher visual complexity, which may support semantic processing, complexity can benefit both item and associative memory. Stimulus properties that enhance item memory can scaffold associative memory in this situation.
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Episodic memory strongly declines in healthy aging, at least partly because of reduced abilities to create and remember associations (associative memory) and to use efficient memory strategies. Several studies have shown that drawing the to-be-remembered material is a reliable encoding tool to enhance memory of individual items (item memory) because it simultaneously integrates elaborative, pictorial, and motoric processes. These processes in isolation can enhance associative memory in older adults. Nevertheless, their simultaneous impact on associative memory has never been investigated in drawing as an encoding tool. We aimed to investigate whether drawing as an encoding tool not only enhances item memory, but whether its benefit extends to associative memory in younger and older adults. Therefore, we tested 101 older and 100 younger participants in two online experiments and one in-person experiment. Using a memory task for unrelated word-pairs, we compared relational drawing and repeatedly writing (non-relational) as encoding tools and assessed immediate recognition memory of items and associations. In Experiment 2, we additionally assessed recognition memory after 1 week. The findings were consistent across the three experiments: while younger participants benefited from drawing over writing in item and associative memory, older participants benefited in item but not in associative memory. The observed effects remained after 1 week. Thus, we could extend the benefit of drawing to relational drawing in associative memory in younger adults. The lack of benefit in older adults' associative memory might be explained by age-related difficulties in benefiting from memory strategies, and in creating and retrieving associations.
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Individual differences in working memory capacity (WMC) are correlated with long-term memory (LTM) differences. Whether this is because high-WMC individuals encode more effectively, resulting in better LTM storage, or because they better retrieve information from LTM is debated. In two experiments, we used Bayesian-hierarchical multinomial modeling to correlate participant-level storage and retrieval processes from LTM recall to WMC abilities estimated from operation and symmetry complex span tasks. In Experiment 1, we presented participants with 20 consecutive words, including semantically associated pairs (e.g., knife and fork), to assess LTM processes. Participants received standard (n = 242) or associative-storage instructions (n = 222) and then completed a free recall task. In Experiment 2, we instructed participants (N = 239) to memorize 40 cue-target words as pairs before completing free and cued recall tasks. Correlations with WMC emerged with storage and retrieval processes and only when an associative storage strategy was instructed (Experiment 1). When associative processing was inherent to the task (Experiment 2), only the associative storage, not the retrieval advantage, replicated. The strategy reports suggest that high-WMC individuals use associative encoding strategies more effectively, resulting in better storage in LTM.
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Neural circuits use homeostatic compensation to achieve consistent behavior despite variability in underlying intrinsic and network parameters. However, it remains unclear how compensation regulates variability across a population of the same type of neurons within an individual and what computational benefits might result from such compensation. We address these questions in the Drosophila mushroom body, the fly's olfactory memory center. In a computational model, we show that under sparse coding conditions, memory performance is degraded when the mushroom body's principal neurons, Kenyon cells (KCs), vary realistically in key parameters governing their excitability. However, memory performance is rescued while maintaining realistic variability if parameters compensate for each other to equalize KC average activity. Such compensation can be achieved through both activity-dependent and activity-independent mechanisms. Finally, we show that correlations predicted by our model's compensatory mechanisms appear in the Drosophila hemibrain connectome. These findings reveal compensatory variability in the mushroom body and describe its computational benefits for associative memory.
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Drosophila melanogaster/fisiología , Memoria/fisiología , Cuerpos Pedunculados/fisiología , Red Nerviosa/fisiología , Animales , Conducta Animal , Simulación por Computador , Cuerpos Pedunculados/citología , Neuronas/clasificación , Neuronas/fisiología , OdorantesRESUMEN
Change is ubiquitous in living beings. In particular, the connectome and neural representations can change. Nevertheless, behaviors and memories often persist over long times. In a standard model, associative memories are represented by assemblies of strongly interconnected neurons. For faithful storage these assemblies are assumed to consist of the same neurons over time. Here we propose a contrasting memory model with complete temporal remodeling of assemblies, based on experimentally observed changes of synapses and neural representations. The assemblies drift freely as noisy autonomous network activity and spontaneous synaptic turnover induce neuron exchange. The gradual exchange allows activity-dependent and homeostatic plasticity to conserve the representational structure and keep inputs, outputs, and assemblies consistent. This leads to persistent memory. Our findings explain recent experimental results on temporal evolution of fear memory representations and suggest that memory systems need to be understood in their completeness as individual parts may constantly change.
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Memoria/fisiología , Neuronas/fisiología , Animales , Homeostasis/fisiología , Modelos Neurológicos , Redes Neurales de la Computación , Plasticidad Neuronal/fisiología , Sinapsis/fisiologíaRESUMEN
Memory traces are believed to be broadly allocated in cerebral cortices and the hippocampus. Mutual synapse innervations among these brain areas are presumably formed in associative memory. In the present study, we have used neuronal tracing by pAAV-carried fluorescent proteins and neuroligin-3 mRNA knockdown by shRNAs to examine the role of neuroligin-3-mediated synapse formation in the interconnection between primary associative memory cells in the sensory cortices and secondary associative memory cells in the hippocampus during the acquisition and memory of associated signals. Our studies show that mutual synapse innervations between the barrel cortex and the hippocampal CA3 region emerge and are upregulated after the memories of associated whisker and odor signals come into view. These synapse interconnections are downregulated by a knockdown of neuroligin-3-mediated synapse linkages. New synapse interconnections and the strengthening of these interconnections appear to endorse the belief in an interaction between the hippocampus and sensory cortices for memory consolidation.
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Hipocampo , Neuroliginas , Corteza Cerebral , Región CA3 Hipocampal , Lóbulo ParietalRESUMEN
Uncovering the mechanisms behind long-term memory is one of the most fascinating open problems in neuroscience and artificial intelligence. Artificial associative memory networks have been used to formalize important aspects of biological memory. Generative diffusion models are a type of generative machine learning techniques that have shown great performance in many tasks. Similar to associative memory systems, these networks define a dynamical system that converges to a set of target states. In this work, we show that generative diffusion models can be interpreted as energy-based models and that, when trained on discrete patterns, their energy function is (asymptotically) identical to that of modern Hopfield networks. This equivalence allows us to interpret the supervised training of diffusion models as a synaptic learning process that encodes the associative dynamics of a modern Hopfield network in the weight structure of a deep neural network. Leveraging this connection, we formulate a generalized framework for understanding the formation of long-term memory, where creative generation and memory recall can be seen as parts of a unified continuum.
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Episodic memory declines with advancing adult age. This decline is particularly pronounced when associations between items and their contexts need to be formed. According to theories of neural communication, the precise coupling of gamma power to the phase of the theta rhythm supports associative memory formation. To investigate whether age differences in associative memory are related to compromised theta-gamma coupling, we took EEG recordings during the encoding phase of an item-context association task. Fifty-eight younger (33 females) and 55 older (24 females) adults studied pictures of objects superimposed on background scenes. In a recognition test, objects were presented on old or new backgrounds, and participants responded if they had seen (1) the object and (2) the object/scene pair. Theta-gamma coupling supported pair memory formation in both age groups. Whereas pair memory was associated with coupling closer to the peak of the theta rhythm, item-only memory was associated with a deviation in phase angle relative to pair memory. Furthermore, a stable relation between coupling phase and pair memory performance demonstrated that coupling closer to the peak is beneficial for associative memory. Critically, older adults' lower pair memory was accompanied by a shift in coupling phase relative to that of younger adults. In concert, the present results are consistent with the hypothesis that decrements in the temporal precision with which gamma power is coupled to a specific theta phase underlie the decline of associative memory in normal cognitive aging.SIGNIFICANCE STATEMENT According to prominent theories of neural communication, the precise coordination of oscillatory activity enables the formation of associative memories. We propose that normal cognitive aging impairs associative memory formation by compromising the temporal precision of neural communication. We show that the coupling of high-frequency gamma power to low-frequency theta phase supports associative memory formation in both younger and older adults, with coupling closer to the theta peak benefitting memory performance. However, compared with younger adults, the coupling phase angle is shifted in time and is more variable in the older adults. We conclude that alterations in the precise timing of theta-gamma coupling contribute to adult age differences in associative memory.
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Memoria Episódica , Ritmo Teta , Anciano , Cognición , Femenino , Humanos , MasculinoRESUMEN
To successfully forage in an environment filled with rewards and threats, animals need to rely on familiar structures of their environment that signal food availability. The central amygdala (CeA) is known to mediate a panoply of consummatory and defensive behaviors, yet how specific activity patterns within CeA subpopulations guide optimal choices is not completely understood. In a paradigm of appetitive conditioning in which mice freely forage for food across a continuum of cues, we found that two major subpopulations of CeA neurons, Somatostatin-positive (CeASst) and protein kinase Cδ-positive (CeAPKCδ) neurons, can assign motivational properties to environmental cues. Although the proportion of food responsive cells was higher within CeASst than CeAPKCδ neurons, only the activities of CeAPKCδ, but not CeASst, neurons were required for learning of contextual food cues. Our findings point to a model in which CeAPKCδ neurons may incorporate stimulus salience together with sensory features of the environment to encode memory of the goal location.SIGNIFICANCE STATEMENT The CeA has a very important role in the formation of memories that associate sensory information with aversive or rewarding representation. Here, we used a conditioned place preference paradigm, where freely moving mice learn to associate external cues with food availability, to investigate the roles of CeA neuron subpopulations. We found that CeASst and CeAPKCδ neurons encoded environmental cues during foraging but only the activities of CeAPKCδ neurons were required for learning of contextual food cues.
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Núcleo Amigdalino Central , Animales , Núcleo Amigdalino Central/fisiología , Condicionamiento Clásico/fisiología , Señales (Psicología) , Ratones , Neuronas/fisiología , RecompensaRESUMEN
Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities, including low-frequency activity, are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate to severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localization responses was abnormally biased by the locations of nontarget items for patients in PTA, suggesting a specific impairment of object and location binding. Slow-wave activity was increased following TBI. Increases in the δ-α ratio indicative of an increase in low-frequency power specifically correlated with binding impairment in working memory. Connectivity changes in TBI did not correlate with binding impairment. Working memory and electrophysiological abnormalities normalized at 6 month follow-up. These results show that patients in PTA show high rates of misbinding that are associated with a pathological shift toward lower-frequency oscillations.SIGNIFICANCE STATEMENT How do we remember what was where? The mechanism by which information (e.g., object and location) is integrated in working memory is a central question for cognitive neuroscience. Following significant head injury, many patients will experience a period of post-traumatic amnesia (PTA) during which this associative binding is disrupted. This may be because of electrophysiological changes in the brain. Using a precision working memory test and resting-state EEG, we show that PTA patients demonstrate impaired binding ability, and this is associated with a shift toward slower-frequency activity on EEG. Abnormal EEG connectivity was observed but was not specific to PTA or binding ability. These findings contribute to both our mechanistic understanding of working memory binding and PTA pathophysiology.