Functional dissociation of hippocampal mechanism during implicit learning based on the domain of associations

Traditionally, the medial temporal lobe (MTL) was linked to explicit or declarative memory in associative learning. However, recent studies have reported MTL involvement even when volunteers are not consciously aware of the learned contingencies. Therefore, the mechanism of the MTL-related learning process cannot be described sufficiently by the explicit/implicit distinction, and the underlying process in the MTL for associative learning needs a more functional characterization. A possible feature that would allow a functional specification also for implicit learning is the nature of the material that is learned. Given that implicit memory tasks often comprise a combination of perceptual and motor learning, we hypothesized that implicit learning of the perceptual but not the motor component entails MTL activation in these studies. To directly test this hypothesis, we designed a purely perceptual and a purely motor variant of the serial reaction time task. In two groups of human volunteers, behavioral results clearly showed that both variants were learned without awareness. Neuronal recordings using fMRI revealed that bilateral hippocampal activation was observed only for implicit learning of the perceptual sequence, not for the motor sequence. This dissociation clearly shows that the functional role of the hippocampus for learning is determined by the domain of the learned association and that the function of the medial temporal lobe system is the processing of contingencies between perceptual features regardless of the explicit or implicit nature of the ensuing memory.     

Achieving enlightenment: what do we know about the implicit learning system and its interaction with explicit knowledge?

Two major memory and learning systems operate in the brain: one for facts and ideas (ie, the declarative or explicit system), one for habits and behaviors (ie, the procedural or implicit system). Broadly speaking these two memory systems can operate either in concert or entirely independently of one another during the performance and learning of skilled motor behaviors. This Special Issue article has two parts. In the first, we present a review of implicit motor skill learning that is largely centered on the interactions between declarative and procedural learning and memory. Because distinct neuroanatomical substrates support unique aspects of learning and memory and thus focal injury can cause impairments that are dependent on lesion location, we also broadly consider which brain regions mediate implicit and explicit learning and memory. In the second part of this article, the interactive nature of these two memory systems is illustrated by the presentation of new data that reveal that both learning implicitly and acquiring explicit knowledge through physical practice lead to motor sequence learning. In our new data, we discovered that for healthy individuals use of the implicit versus explicit memory system differently affected variability of performance during acquisition practice; variability was higher early in practice for the implicit group and later in practice for the acquired explicit group. Despite the difference in performance variability, by retention both groups demonstrated comparable change in tracking accuracy and thus, motor sequence learning. Clinicians should be aware of the potential effects of implicit and explicit interactions when designing rehabilitation interventions, particularly when delivering explicit instructions before task practice, working with individuals with focal brain damage, and/or adjusting therapeutic parameters based on acquisition performance variability.     

The role of the basal ganglia and its cortical connections in sequence learning: Evidence from implicit and explicit sequence learning in Parkinson's disease

Implicit (unconscious/incidental) and explicit (conscious/intentional) learning are considered to have distinct neural substrates. It is proposed that implicit learning is mediated by the basal ganglia (BG), while explicit learning has been linked to the medial temporal lobes (MTL). To test such a dissociation we investigated implicit and explicit sequence learning in Parkinson's disease (PD), a disorder characterized by striatal dysfunction. We studied both implicit and explicit learning of a 12-item sequence of target locations in 13 PD patients and 15 age-matched controls. In the implicit sequence learning task all participants completed 10 blocks of a probabilistic serial reaction time (SRT) task in which they were exposed to the sequence without explicit knowledge of it. Participants also completed between 1 and 10 blocks of an explicit sequence learning task in which the sequence was learned deliberately by trial-and-error. Both implicit and explicit sequence learning were significantly impaired in PD patients compared to controls. The results indicate that, in addition to playing a role in implicit sequence learning, the BG and its frontal projections are also involved in explicit sequence learning.     

Allocentric memory impaired and egocentric memory intact as assessed by virtual reality in recent-onset schizophrenia

Present evidence suggests that schizophrenia is associated with explicit memory deficits, whereas implicit memory seems to be largely preserved. Virtual reality studies on declarative allocentric memory in schizophrenia are rare, and studies on implicit egocentric memory in schizophrenia are lacking. However, virtual realities have a major advantage for the assessment of spatial navigation and memory formation, as computer-simulated first-person environments can simulate navigation in a large-scale space. Twenty-five subjects with recent-onset schizophrenia were compared with 25 healthy matched control subjects on two virtual reality tasks affording the navigation and learning of a virtual park (allocentric memory) and a virtual maze (egocentric memory). Compared with control subjects, schizophrenia subjects were significantly impaired in learning the virtual park. However, schizophrenia subjects were as able as control subjects to learn the virtual maze. Stronger disorganized symptoms of schizophrenia subjects were significantly related to more errors on the virtual maze. It is concluded that egocentric spatial learning adds to the many other implicit cognitive skills being largely preserved in schizophrenia. Possibly, the more global neural network supporting egocentric spatial learning is less affected than the declarative hippocampal memory system in early stages of schizophrenia and may offer opportunities for compensation in the presence of focal deficits.     

Understanding the Neural Bases of Implicit and Statistical Learning

Both implicit learning and statistical learning focus on the ability of learners to pick up on patterns in the environment. It has been suggested that these two lines of research may be combined into a single construct of “implicit statistical learning.” However, by comparing the neural processes that give rise to implicit versus statistical learning, we may determine the extent to which these two learning paradigms do indeed describe the same core mechanisms. In this review, we describe current knowledge about neural mechanisms underlying both implicit learning and statistical learning, highlighting converging findings between these two literatures. A common thread across all paradigms is that learning is supported by interactions between the declarative and nondeclarative memory systems of the brain. We conclude by discussing several outstanding research questions and future directions for each of these two research fields. Moving forward, we suggest that the two literatures may interface by defining learning according to experimental paradigm, with “implicit learning” reserved as a specific term to denote learning without awareness, which may potentially occur across all paradigms. By continuing to align these two strands of research, we will be in a better position to characterize the neural bases of both implicit and statistical learning, ultimately improving our understanding of core mechanisms that underlie a wide variety of human cognitive abilities.     

Comparison of implicit memory encoding paradigms for the activation of mediotemporal structures

The medial temporal lobes (MTLs) are essential for both encoding and retrieval processes in declarative memory. In addition, they are a frequent seizure focus for medically refractory epilepsy. One of the major side effects of MTL resection is a decline in memory functions. Most functional imaging paradigms have been developed to find preoperative measures that, to obtain a prognosis of postoperative memory performance, employ explicit memory encoding strategies to elicit MTL activation, and require a great amount of cognitive effort. We applied three different implicit encoding tasks, which require less effort and time, to a group of healthy subjects. We found left-lateralized activation for verbal stimuli, bilateral activation for pictures, and right-lateralized activation for faces. The present study shows that even with an implicit memory-encoding paradigm, a lateralized activation of MTL structures can be achieved. This may lead to paradigms for routine clinical application that require less cognitive effort and time on the part of patients.     

What is a suggestion? The neuroscience of implicit processing heuristics in therapeutic hypnosis and psychotherapy

Neuroscience and bioinformatics research on activity-dependent gene expression and brain plasticity in memory and learning are used to reconceptualize a fundamental question of therapeutic hypnosis, "What is a suggestion?" John Kihlstrom's cognitive-behavioral perspective of implicit (unconscious) and explicit (conscious) memory and Eric Kandel's Nobel Prize winning neurobiological research are integrated for a 30-year update of Milton H. Erickson's "neuro-psycho-physiology" of therapeutic hypnosis. Implicit processing heuristics are proposed as a more general framework for Erickson's concept of permissive indirect suggestions in therapeutic hypnosis and psychotherapy. These perspectives are illustrated by utilizing implicit processing heuristics to facilitate the four-stage creative process in converting implicit to explicit memory in a brain-damaged patient.     

Implicit and explicit memory after focal thalamic lesions.

BACKGROUND: Lesions of the thalamus interfere with cognitive functions mainly in the area of declarative learning and memory. Little is known about the role the thalamus plays in implicit learning. OBJECTIVE: To study explicit and implicit learning and memory in subjects with thalamic lesions and to analyze the influence of lesion characteristics on cognitive performance. METHODS: The authors studied the performance of 15 subjects with focal thalamic infarction or hemorrhage on a comprehensive neuropsychological test battery focusing on tests of explicit memory and learning of a nondeclarative motor skill. Subjects with thalamic lesions were compared to 15 healthy matched control subjects and to a clinical control group of 22 subjects who had sustained basal ganglia lesions. RESULTS: Subjects with thalamic lesions showed well-preserved intellectual and executive functions but demonstrated deficits on measures of attention and psychomotor speed, explicit memory, and implicit visuomotor sequence learning. Lesion size in the thalamus was clearly related to subjects' long-term explicit memory performance. However, few of the neuropsychological deficits found seemed specific to the long-term neuropsychological outcome of focal thalamic infarctions. Subjects with lesions in the basal ganglia demonstrated similar deficits. CONCLUSIONS: Focal subcortical lesions in the thalamus and the basal ganglia lead to a similar profile of neuropsychological deficits. Lesions in the thalamus not only affect declarative memory but also interfere with nondeclarative motor skill learning.     

Effect of handedness on fMRI activation in the medial temporal lobe during an auditory verbal memory task

Several studies have shown marked differences in the neural localization of language functions in the brains of left-handed individuals when compared with right-handers. Previous experiments involving functional lateralization have demonstrated cerebral blood flow patterns that differ concordantly with subject handedness while performing language-related tasks. The effect of handedness on function in specific stages of memory processing, however, is a largely unexplored area. We used a paired-associates verbal memory task to elicit activation of neural areas related to declarative memory, examining the hypothesis that there are differences in activation in the medial temporal lobe (MTL) between handedness groups. 15 left-handed and 25 right-handed healthy adults were matched for all major demographic and neuropsychological variables. Functional and structural imaging data were acquired and analyzed for group differences within MTL subregions. Our results show that activation of the MTL during declarative memory processing varies with handedness. While both groups showed activation in left and right MTL subregions, the left-handed group showed a statistically significant increase in the left hippocampus and amygdala during both encoding and recall. No increases in activation were found in the right-handed group. This effect was found in the absence of any differences in performance on the verbal memory task, structural volumetric disparities, or functional asymmetries. This provides evidence of functional differences between left-handers and right-handers, which extends to declarative memory processes.     

Severity of explicit memory impairment due to Alzheimer’s disease improves effectiveness of implicit learning

Background Consistent evidence from human and experimental animals studies indicates that memory is organized into two relatively independent systems with different functions and brain mechanisms. The explicit memory system, dependent on the hippocampus and adjacent medial temporal lobe structures, refers to conscious knowledge acquisition and intentional recollection of previous experiences. The implicit memory system, dependent on the striatum, refers to learning of complex information without awareness or intention. The functioning of implicit memory can be observed in progressive, gradual improvement across many trials in performance on implicit learning tasks. The influence of explicit memory on implicit memory has not been precisely identified yet. According to data from some studies, explicit memory seems to exhibit no influence on implicit memory,whereas the other studies indicate that explicit memory may inhibit or facilitate implicit memory. Objectives The analysis of performance on implicit learning tasks in patients with different severity of explicit memory impairment due to Alzheimer’s disease allows one to identify the potential influence of the explicit memory system on the implicit memory system. Patients and methods 51 patients with explicit memory impairment due to Alzheimer’s disease (AD) and 36 healthy controls were tested. Explicit memory was examined by means of a battery of neuropsychological tests. Implicit habit learning was examined on probabilistic classification task (weather prediction task). Results Patients with moderate explicit memory impairment performed the implicit task significantly better than those with mild AD and controls. Conclusion Results of our study support the hypothesis of competition between the implicit and explicit memory systems in humans.     

Intact implicit learning in schizophrenia

OBJECTIVE: Schizophrenia impairs performance on explicit, but not implicit, memory tasks, indicating that conscious awareness at retrieval is a critical determinant of impaired memory. The authors investigated implicit learning, i.e., knowledge acquisition in the absence of conscious awareness, in patients with schizophrenia. METHOD: An artificial grammar learning task was used to assess implicit learning in 48 patients with schizophrenia and 24 healthy comparison subjects. The subjects were first presented with letter strings that were generated according to the rules of a finite-state grammar paradigm. They were then required to indicate whether new letter strings were "grammatical," depending on whether or not the strings corresponded to the rules. IQ, working memory, explicit memory, verbal fluency, and speed of processing were also assessed. RESULTS: Patients performed significantly worse than the comparison subjects on cognitive tasks that assessed episodic memory, verbal fluency, working memory, and speed of processing. In contrast, patients classified as being correct more grammatical than nongrammatical letter strings, and the magnitude of the difference was similar to that observed in healthy comparison subjects. CONCLUSIONS: Implicit learning, as assessed with an artificial grammar learning task, is intact in patients with schizophrenia. Conscious awareness might be a critical determinant of memory impairment both at encoding and at retrieval.     

The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB

ABSTRACT: The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.     

Columnar distribution of activity dependent gabaergic depolarization in sensorimotor cortical neurons

The analysis of the contributions to synaptic plasticity and memory of cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB has recruited the efforts of many laboratories all over the world. These are six key steps in the molecular biological delineation of short-term memory and its conversion to long-term memory for both implicit (procedural) and explicit (declarative) memory. I here first trace the background for the clinical and behavioral studies of implicit memory that made a molecular biology of memory storage possible, and then detail the discovery and early history of these six molecular steps and their roles in explicit memory.     

Primary motor and premotor cortex in implicit sequence learning - evidence for competition between implicit and explicit human motor memory systems

Implicit and explicit memory systems for motor skills compete with each other during and after motor practice. Primary motor cortex (M1) is known to be engaged during implicit motor learning, while dorsal premotor cortex (PMd) is critical for explicit learning. To elucidate the neural substrates underlying the interaction between implicit and explicit memory systems, adults underwent a randomized crossover experiment of anodal transcranial direct current stimulation (AtDCS) applied over M1, PMd or sham stimulation during implicit motor sequence (serial reaction time task, SRTT) practice. We hypothesized that M1‐AtDCS during practice will enhance online performance and offline learning of the implicit motor sequence. In contrast, we also hypothesized that PMd‐AtDCS will attenuate performance and retention of the implicit motor sequence. Implicit sequence performance was assessed at baseline, at the end of acquisition (EoA), and 24 h after practice (retention test, RET). M1‐AtDCS during practice significantly improved practice performance and supported offline stabilization compared with Sham tDCS. Performance change from EoA to RET revealed that PMd‐AtDCS during practice attenuated offline stabilization compared with M1‐AtDCS and sham stimulation. The results support the role of M1 in implementing online performance gains and offline stabilization for implicit motor sequence learning. In contrast, enhancing the activity within explicit motor memory network nodes such as the PMd during practice may be detrimental to offline stabilization of the learned implicit motor sequence. These results support the notion of competition between implicit and explicit motor memory systems and identify underlying neural substrates that are engaged in this competition.     

Probabilistic classification learning with corrective feedback is selectively impaired in early Huntington's disease--evidence for the role of the striatum in learning with feedback

In general, declarative learning is associated with the activation of the medial temporal lobes (MTL), while the basal ganglia (BG) are considered the substrate for procedural learning. More recently it has been demonstrated the distinction of these systems may not be as absolute as previously thought and that not only the explicit or implicit nature of the memory task alone is important for the distinction of MTL or BG systems. Nevertheless, patients with BG dysfunction - such as patients with Parkinson's disease (PD) or Huntington's disease (HD) - are considered to be impaired at implicit learning. However, a more recent study demonstrated that one implicit learning task, probabilistic classification learning (examples include the weather prediction (WPT) and Mr. Potato Head tasks) is only impaired in PD when it involves learning with corrective feedback (FB) but not when it involves learning in a paired associate (PA) manner, without feedback. Therefore, it has been argued that the presence of feedback rather than the implicit nature of these tasks determines whether or not the BG are recruited. As patients with HD as well as those with PD, have also been shown to be impaired on the standard FB based version of probabilistic classification learning, the question remains as to whether or not there is a similar selective deficit in FB but not PA based probabilistic classification learning in HD. 18 patients with early HD and 18 healthy controls completed FB and PA versions of the WPT task. Relative to controls, HD patients were selectively impaired at WPT learning with feedback. These findings are consistent with previous evidence from studies of probabilistic classification learning in PD. Unlike PD, selective deficits in WPT learning in HD cannot be attributed to the effects of dopaminergic medication and must be directly related to BG dysfunction; for instance even in early HD, only 50% of the neurons in the medial head of caudate remain. We conclude that the striatum is important for WPT learning with feedback. Our findings are consistent with imaging evidence showing recruitment of the caudate during FB based WPT learning, while the MTL is associated with PA based learning.     

Learning of writing letter-like sequences in children with physical and multiple disabilities

This study compared implicit and explicit learning instructions in hand writing. Implicit learning is the ability to acquire a new skill without a corresponding increase in knowledge about the skill. In contrast, explicit learning uses declarative knowledge to build up a set of performance rules that guide motor performance or skills. Explicit learning is dependent on working memory, implicit learning is not. Therefore, implicit learning was expected to be easier than explicit learning in children in special education, given their expected compromised working memory. Two groups of children (5–12 years) participated, children in special education with physical or multiple disabilities (study group, n = 22), and typically developing controls (n = 32). Children learned to write letter-like patterns on a digitizer by tracking a moving target (implicitly) and verbal instruction (explicitly). We further tested visual working memory, visual-motor integration, and gross manual dexterity. Learning curves were similar for both groups in both conditions; children in the study group did learn both implicitly and explicitly. Motor performance was related to the writing task. In contrast to our hypothesis, visual working memory was not an important factor in the explicit condition. These results shed new light on the conceptual difference between implicit and explicit learning, and the role of working memory therein.     

Does the cholinesterase inhibitor, donepezil, benefit both declarative and non-declarative processes in mild to moderate Alzheimer's disease?

Previous research suggests separate neural networks for implicit (non-declarative) and explicit (declarative) memory processes. A core cognitive impairment in mild to moderate Alzheimer's disease (AD) is a pronounced declarative memory and learning deficit with relative preservation of non-declarative memory. Cholinesterase inhibitors has been purported to enhance cognitive function, and previous clinical trials consistently showed that donepezil, a reversible inhibitor of acetylcholinesterase (AChE), led to statistically significant improvements in cognition and patient function. This prospective pilot study is a randomized, double blind, placebo-controlled clinical trial investigating 10 patients with AD. Our purpose was to examine the relationship between declarative and non-declarative capability with particular emphasis on implicit sequence learning. Patients were assessed at baseline and again at 4-weeks. After participants' baseline data were obtained, each was double-blindly randomized to one of two groups: donepezil or placebo. At baseline participants were tested with two outcome measures (Serial Reaction Time Task, Alzheimer's Disease Assessment Scale-Cognitive Subscale). Participants were given either 5 mg donepezil or an identically appearing placebo to be taken nightly for 4 weeks (28 tablets), and then retested. The donepezil group demonstrated a greater likelihood of increases in both non-declarative and declarative processes. The placebo group was mixed without clearly definable trends or patterns. When the data were examined for coincidental changes in the two outcome measures together they are suggestive of a benefit from donepezil treatment for non-declarative and declarative processes.     

Nonconscious formation and reactivation of semantic associations by way of the medial temporal lobe

A successful strategy to memorize unrelated items is to associate them semantically. This learning method is typical for declarative memory and depends on the medial temporal lobe (MTL). Yet, only a small fraction of perceived items emerge into conscious awareness and receive the status of representations in declarative memory. This functional magnetic resonance imaging (fMRI) study tackled the mnemonic fate of unrelated item pairs processed without conscious awareness. Stimuli consisted of a face and a written profession (experimental condition) or of a face (control condition) exposed very briefly between pattern masks. Although the participants were unaware of the stimuli, activity in the hippocampus and perirhinal cortex was changed in the experimental versus the control condition; perirhinal activity changes correlated with the reaction time measure of the later nonconscious retrieval. For retrieval, the previously presented faces were shown again, this time for conscious inspection. The task was to guess the professional category of each face. This task was to induce a nonconscious retrieval of previously formed face-profession associations. Remarkably, activity in the hippocampus and perirhinal cortex was enhanced when subjects were confronted with faces from the experimental versus the control condition. The degree of hippocampal and perirhinal activation changes correlated with the reaction time measure of nonconscious retrieval. Together, our findings suggest that new semantic associations can be formed and retrieved by way of the medial temporal lobe without awareness of the associations or its components at encoding or any awareness that one is remembering at retrieval.     

Perirhinal and hippocampal contributions to visual recognition memory can be distinguished from those of occipito-temporal structures based on conscious awareness of prior occurrence

The ability of humans to distinguish consciously between new and previously encountered objects can be probed with visual recognition memory tasks that require explicit old-new discriminations. Medial temporal-lobe (MTL) lesions impair performance on such tasks. Within the MTL, both perirhinal cortex and the hippocampus have been implicated. Cognitive processes can also be affected by past object encounters in the absence of conscious recognition, as in repetition priming tasks. Past functional neuroimaging findings in healthy individuals suggest that even in tasks that require conscious recognition decisions for visual stimuli, posterior cortical structures in the ventral visual pathway distinguish between old and new objects at a nonconscious level. Conclusive evidence that differentiates the neural underpinnings of conscious from nonconscious processes in recognition memory, however, is still missing. In particular, functional magnetic resonance imaging (fMRI) findings for the MTL have been inconsistent towards this end. In the present fMRI study, we tested whether perirhinal and hippocampal contributions to recognition memory can be distinguished from those of occipito-temporal structures in the ventral visual pathway based on the participants' reported conscious awareness of prior occurrence. Images of objects with a large degree of feature overlap served as stimuli; they were selected to ensure an involvement of perirhinal cortex in the present recognition task, based on evidence from past lesion-based research. We found that both perirhinal cortex and occipito-temporal cortex showed a differential old-new response that reflected a repetition-related decrease in activity (i.e., new > old). Whereas in perirhinal cortex this decrease was observed with respect to whether subjects reported objects to be old or new, irrespective of the true item status, in occipito-temporal cortex it occurred in relation to whether objects were truly old or new, irrespective of the participants' conscious reports. Hippocampal responses differed in their exact pattern from those of perirhinal cortex, but were also related to the conscious recognition reports. These results indicate that both perirhinal and hippocampal contributions can be distinguished from those of occipito-temporal structures in the ventral visual pathway based on the participants' reported conscious awareness of prior occurrence.     

Event-related potential correlates of declarative and non-declarative sequence knowledge

The goal of the present study was to demonstrate that declarative and non-declarative knowledge acquired in an incidental sequence learning task contributes differentially to memory retrieval and leads to dissociable ERP signatures in a recognition memory task. For this purpose, participants performed a sequence learning task and were classified as verbalizers, partial verbalizers, or nonverbalizers according to their ability to verbally report the systematic response sequence. Thereafter, ERPs were recorded in a recognition memory task time-locked to sequence triplets that were either part of the previously learned sequence or not. Although all three groups executed old sequence triplets faster than new triplets in the recognition memory task, qualitatively distinct ERP patterns were found for participants with and without reportable knowledge. Verbalizers and, to a lesser extent, partial verbalizers showed an ERP correlate of recollection for parts of the incidentally learned sequence. In contrast, nonverbalizers showed a different ERP effect with a reverse polarity that might reflect priming. This indicates that an ensemble of qualitatively different processes is at work when declarative and non-declarative sequence knowledge is retrieved. By this, our findings favor a multiple-systems view postulating that explicit and implicit learning are supported by different and functionally independent systems.