Segregating the functions of human hippocampus

It is now accepted that hippocampal lesions impair episodic memory. However, the precise functional role of the hippocampus in episodic memory remains elusive. Recent functional imaging data implicate the hippocampus in processing novelty, a finding supported by human in vivo recordings and event-related potential studies. Here we measure hippocampal responses to novelty, using functional MRI (fMRI), during an item-learning paradigm generated from an artificial grammar system. During learning, two distinct types of novelty were periodically introduced: perceptual novelty, pertaining to the physical characteristics of stimuli (in this case visual characteristics), and exemplar novelty, reflecting semantic characteristics of stimuli (in this case grammatical status within a rule system). We demonstrate a left anterior hippocampal response to both types of novelty and adaptation of these responses with stimulus familiarity. By contrast to these novelty effects, we also show bilateral posterior hippocampal responses with increasing exemplar familiarity. These results suggest a functional dissociation within the hippocampus with respect to the relative familiarity of study items. Neural responses in anterior hippocampus index generic novelty, whereas posterior hippocampal responses index familiarity to stimuli that have behavioral relevance (i.e., only exemplar familiarity). These findings add to recent evidence for functional segregation within the human hippocampus during learning.

Functional neuroanatomical double dissociation of mnemonic and executive control processes contributing to working memory performance

We used event-related functional MRI to investigate the neural bases of two categories of mental processes believed to contribute to performance of an alphabetization working memory task: memory storage and memory manipulation. Our delayed-response tasks required memory for the identity and position-in-the-display of items in two- or five-letter memory sets (to identify load-sensitive regions) or memory for the identity and relative position-in-the-alphabet of items in five-letter memory sets (to identify manipulation-sensitive regions). Results revealed voxels in the left perisylvian cortex of five of five subjects showing load sensitivity (as contrasted with alphabetization-sensitive voxels in this region in only one subject) and voxels of dorsolateral prefrontal cortex in all subjects showing alphabetization sensitivity (as contrasted with load-sensitive voxels in this region in two subjects). This double dissociation was reliable at the group level. These data are consistent with the hypothesis that the nonmnemonic executive control processes that can contribute to working memory function are primarily prefrontal cortex-mediated whereas mnemonic processes necessary for working memory storage are primarily posteriorly mediated. More broadly, they support the view that working memory is a faculty that arises from the coordinated interaction of computationally and neuroanatomically dissociable processes.

Parsing executive processes: Strategic vs. evaluative functions of the anterior cingulate cortex

Event-related functional MRI and a version of the Stroop color naming task were used to test two conflicting theories of anterior cingulate cortex (ACC) function during executive processes of cognition. A response-related increase in ACC activity was present when strategic processes were less engaged, and conflict high, but not when strategic processes were engaged and conflict reduced. This is inconsistent with the widely held view that the ACC implements strategic processes to reduce cognitive conflicts, such as response competition. Instead, it suggests that the ACC serves an evaluative function, detecting cognitive states such as response competition, which may lead to poor performance, and representing the knowledge that strategic processes need to be engaged.

The roles of prefrontal brain regions in components of working memory: Effects of memory load and individual differences

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects’ memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

Memory's echo: Vivid remembering reactivates sensory-specific cortex

A fundamental question in human memory is how the brain represents sensory-specific information during the process of retrieval. One hypothesis is that regions of sensory cortex are reactivated during retrieval of sensory-specific information (1). Here we report findings from a study in which subjects learned a set of picture and sound items and were then given a recall test during which they vividly remembered the items while imaged by using event-related functional MRI. Regions of visual and auditory cortex were activated differentially during retrieval of pictures and sounds, respectively. Furthermore, the regions activated during the recall test comprised a subset of those activated during a separate perception task in which subjects actually viewed pictures and heard sounds. Regions activated during the recall test were found to be represented more in late than in early visual and auditory cortex. Therefore, results indicate that retrieval of vivid visual and auditory information can be associated with a reactivation of some of the same sensory regions that were activated during perception of those items.

The role of prefrontal cortex and posterior parietal cortex in task switching

Human ability to switch from one cognitive task to another involves both endogenous preparation without an external stimulus and exogenous adjustment in response to the external stimulus. In an event-related functional MRI study, participants performed pairs of two tasks that are either the same (task repetition) or different (task switch) from each other. On half of the trials, foreknowledge about task repetition or task switch was available. On the other half, it was not. Endogenous preparation seems to involve lateral prefrontal cortex (BA 46/45) and posterior parietal cortex (BA 40). During preparation, higher activation increases in inferior lateral prefrontal cortex and superior posterior parietal cortex were associated with foreknowledge than with no foreknowledge. Exogenous adjustment seems to involve superior prefrontal cortex (BA 8) and posterior parietal cortex (BA 39/40) in general. During a task switch with no foreknowledge, activations in these areas were relatively higher than during a task repetition with no foreknowledge. These results suggest that endogenous preparation and exogenous adjustment for a task switch may be independent processes involving different brain areas.

Functional neuroimaging studies of encoding, priming, and explicit memory retrieval

Human functional neuroimaging techniques provide a powerful means of linking neural level descriptions of brain function and cognition. The exploration of the functional anatomy underlying human memory comprises a prime example. Three highly reliable findings linking memory-related cognitive processes to brain activity are discussed. First, priming is accompanied by reductions in the amount of neural activation relative to naive or unprimed task performance. These reductions can be shown to be both anatomically and functionally specific and are found for both perceptual and conceptual task components. Second, verbal encoding, allowing subsequent conscious retrieval, is associated with activation of higher order brain regions including areas within the left inferior and dorsal prefrontal cortex. These areas also are activated by working memory and effortful word generation tasks, suggesting that these tasks, often discussed as separable, might rely on interdependent processes. Finally, explicit (intentional) retrieval shares much of the same functional anatomy as the encoding and word generation tasks but is associated with the recruitment of additional brain areas, including the anterior prefrontal cortex (right > left). These findings illustrate how neuroimaging techniques can be used to study memory processes and can both complement and extend data derived through other means. More recently developed methods, such as event-related functional MRI, will continue this progress and may provide additional new directions for research.

Imaging the functioning human brain

One of the most exciting methodological advances for brain research field arises in functional brain imaging, which enables us to localize and characterize neural activity and biochemical events in the living human brain. Recently developed event-related functional MRI makes it possible to visualize the brain activity associated with cognitive processes with the temporal resolution of the hemodynamic response. In addition, the high sensitivity and selectivity of positron-emission tomography allow us to probe the neurochemical processes at the molecular level. Positron-emission tomography also has been applied to investigate the effects of therapeutic drugs as well as the effects of drugs of abuse.

Brain activity evidence for recognition without recollection after early hippocampal damage

Amnesic patients with early and seemingly isolated hippocampal injury show relatively normal recognition memory scores. The cognitive profile of these patients raises the possibility that this recognition performance is maintained mainly by stimulus familiarity in the absence of recollection of contextual information. Here we report electrophysiological data on the status of recognition memory in one of the patients, Jon. Jon's recognition of studied words lacks the event-related potential (ERP) index of recollection, viz., an increase in the late positive component (500–700 ms), under conditions that elicit it reliably in normal subjects. On the other hand, a decrease of the ERP amplitude between 300 and 500 ms, also reliably found in normal subjects, is well preserved. This so-called N400 effect has been linked to stimulus familiarity in previous ERP studies of recognition memory. In Jon, this link is supported by the finding that his recognized and unrecognized studied words evoked topographically distinct ERP effects in the N400 time window. These data suggest that recollection is more dependent on the hippocampal formation than is familiarity, consistent with the view that the hippocampal formation plays a special role in episodic memory, for which recollection is so critical.

Role of cortical N-methyl-D-aspartate receptors in auditory sensory memory and mismatch negativity generation: implications for schizophrenia.

Working memory refers to the ability of the brain to store and manipulate information over brief time periods, ranging from seconds to minutes. As opposed to long-term memory, which is critically dependent upon hippocampal processing, critical substrates for working memory are distributed in a modality-specific fashion throughout cortex. N-methyl-D-aspartate (NMDA) receptors play a crucial role in the initiation of long-term memory. Neurochemical mechanisms underlying the transient memory storage required for working memory, however, remain obscure. Auditory sensory memory, which refers to the ability of the brain to retain transient representations of the physical features (e.g., pitch) of simple auditory stimuli for periods of up to approximately 30 sec, represents one of the simplest components of the brain working memory system. Functioning of the auditory sensory memory system is indexed by the generation of a well-defined event-related potential, termed mismatch negativity (MMN). MMN can thus be used as an objective index of auditory sensory memory functioning and a probe for investigating underlying neurochemical mechanisms. Monkeys generate cortical activity in response to deviant stimuli that closely resembles human MMN. This study uses a combination of intracortical recording and pharmacological micromanipulations in awake monkeys to demonstrate that both competitive and noncompetitive NMDA antagonists block the generation of MMN without affecting prior obligatory activity in primary auditory cortex. These findings suggest that, on a neurophysiological level, MMN represents selective current flow through open, unblocked NMDA channels. Furthermore, they suggest a crucial role of cortical NMDA receptors in the assessment of stimulus familiarity/unfamiliarity, which is a key process underlying working memory performance.

Eye Gaze Behavior at Turn Transition: How Aphasic Patients Process Speakers' Turns during Video Observation

The human turn-taking system regulates the smooth and precise exchange of speaking turns during face-to-face interaction. Recent studies investigated the processing of ongoing turns during conversation by measuring the eye movements of noninvolved observers. The findings suggest that humans shift their gaze in anticipation to the next speaker before the start of the next turn. Moreover, there is evidence that the ability to timely detect turn transitions mainly relies on the lexico-syntactic content provided by the conversation. Consequently, patients with aphasia, who often experience deficits in both semantic and syntactic processing, might encounter difficulties to detect and timely shift their gaze at turn transitions. To test this assumption, we presented video vignettes of natural conversations to aphasic patients and healthy controls, while their eye movements were measured. The frequency and latency of event-related gaze shifts, with respect to the end of the current turn in the videos, were compared between the two groups. Our results suggest that, compared with healthy controls, aphasic patients have a reduced probability to shift their gaze at turn transitions but do not show significantly increased gaze shift latencies. In healthy controls, but not in aphasic patients, the probability to shift the gaze at turn transition was increased when the video content of the current turn had a higher lexico-syntactic complexity. Furthermore, the results from voxel-based lesion symptom mapping indicate that the association between lexico-syntactic complexity and gaze shift latency in aphasic patients is predicted by brain lesions located in the posterior branch of the left arcuate fasciculus. Higher lexico-syntactic processing demands seem to lead to a reduced gaze shift probability in aphasic patients. This finding may represent missed opportunities for patients to place their contributions during everyday conversation.

Intracranial EEG correlates of implicit relational inference within the hippocampus

Drawing inferences from past experiences enables adaptive behavior in future situations. Inference has been shown to depend on hippocampal processes. Usually, inference is considered a deliberate and effortful mental act which happens during retrieval, and requires the focus of our awareness. Recent fMRI studies hint at the possibility that some forms of hippocampus-dependent inference can also occur during encoding and possibly also outside of awareness. Here, we sought to further explore the feasibility of hippocampal implicit inference, and specifically address the temporal evolution of implicit inference using intracranial EEG. Presurgical epilepsy patients with hippocampal depth electrodes viewed a sequence of word pairs, and judged the semantic fit between two words in each pair. Some of the word pairs entailed a common word (e.g.,‘winter - red’, ‘red - cat’) such that an indirect relation was established in following word pairs (e.g, ‘winter - cat’). The behavioral results suggested that drawing inference implicitly from past experience is feasible because indirect relations seemed to foster ‘fit’ judgments while the absence of indirect relations fostered 'do not fit' judgments, even though the participants were unaware of the indirect relations. A event-related potential (ERP) difference emerging 400 ms post-stimulus was evident in the hippocampus during encoding, suggesting that indirect relations were already established automatically during encoding of the overlapping word pairs. Further ERP differences emerged later post-stimulus (1500 ms), were modulated by the participants' responses and were evident during encoding and test. Furthermore, response-locked ERP effects were evident at test. These ERP effects could hence be a correlate of the interaction of implicit memory with decision-making. Together, the data map out a time-course in which the hippocampus automatically integrates memories from discrete but related episodes to implicitly influence future decision making.

The role of semantic context and attentional resource distribution in semantic comprehension in Swedish pre-schoolers

Research on semantic processing focused mainly on isolated units in language, which does not reflect the complexity of language. In order to understand how semantic information is processed in a wider context, the first goal of this thesis was to determine whether Swedish pre-school children are able to comprehend semantic context and if that context is semantically built up over time. The second goal was to investigate how the brain distributes attentional resources by means of brain activation amplitude and processing type. Swedish preschool children were tested in a dichotic listening task with longer children’s narratives. The development of event-related potential N400 component and its amplitude were used to investigate both goals. The decrease of the N400 in the attended and unattended channel indicated semantic comprehension and that semantic context was built up over time. The attended stimulus received more resources, processed the stimuli in more of a top-down manner and displayed prominent N400 amplitude in contrast to the unattended stimulus. The N400 and the late positivity were more complex than expected since endings of utterances longer than nine words were not accounted for. More research on wider linguistic context is needed in order to understand how the human brain comprehends natural language. 

Processing of English words with fine acoustic contrasts and simple tones: A mismatch negativity study

The purpose of this study was to compare the robustness of the event-related potential (ERP) response, called the mismatch negativity (MMN), when elicited by simple tone stimuli (differing in frequency, duration, or intensity) and speech stimuli (CV nonword contrast /de:/ vs. /ge:/ and CV word contrast /deI/ vs. /geI/). The study was conducted using 30 young adult subjects (Groups A and B; n = 15 each). The speech stimuli were presented to Group A at a stimulus onset asynchrony (SOA) of 610 msec and to Group B at an SOA of 900 msec. The tone stimuli were presented to both groups at an SOA of 610 msec. MMN responses were elicited by the simple tone stimuli (66.7%-96.7% of subjects with MMN "present," or significantly different from zero, p < 0.05) but not the speech stimuli (10% subjects with MMN present for nonwords, 10% for words). The length of the SOA (610 msec or 900 msec) had no effect on the ability to obtain consistent MMN responses to the speech stimuli. The results indicated a lack of robust MMN elicited by speech stimuli with fine acoustic contrasts under carefully controlled methodological conditions. The implications of these results are discussed in relation to conflicting reports in the literature of speech-elicited MMNs, and the importance of appropriate methodological design in MMN studies investigating speech processing in normal and pathological populations.