Patients with schizophrenia perform poorly on cognitive skill learning tasks. This study is the first to investigate the neural basis of impairment in cognitive skill learning in first-degree adolescent relatives of patients with schizophrenia. We used functional magnetic resonance imaging to compare activation in 16 adolescent siblings of patients with childhood-onset schizophrenia (COS) and 45 adolescent controls to determine whether impaired cognitive skill learning in individuals with genetic risk for schizophrenia was associated with specific patterns of neural activation. The siblings of patients with COS were severely impaired on the Weather Prediction Task (WPT) and showed a relative deactivation in frontal regions and in the striatum after extensive training on the WPT compared with controls. These differences were not accounted for by performance differences in the 2 groups. The results suggest that corticostriatal dysfunction may be part of the liability for schizophrenia.
cognitive skill learning; striatal dysfunction; genetic risk; fMRI
A number of prior fMRI studies have focused on the ways in which the midbrain dopaminergic reward system co-activates with hippocampus to potentiate memory for valuable items. However, another means by which people could selectively remember more valuable to-be-remembered items is to be selective in their use of effective but effortful encoding strategies. To broadly examine the neural mechanisms of value on subsequent memory, we used fMRI to examine how differences in brain activity at encoding as a function of value relate to subsequent free recall for words. Each word was preceded by an arbitrarily assigned point value, and participants went through multiple study-test cycles with feedback on their point total at the end of each list, allowing for sculpting of cognitive strategies. We examined the correlation between value-related modulation of brain activity and participants’ selectivity index, a measure of how close participants were to their optimal point total given the number of items recalled. Greater selectivity scores were associated with greater differences in activation of semantic processing regions, including left inferior frontal gyrus and left posterior lateral temporal cortex, during encoding of high-value words relative to low-value words. Although we also observed value-related modulation within midbrain and ventral striatal reward regions, our fronto-temporal findings suggest that strategic engagement of deep semantic processing may be an important mechanism for selectively encoding valuable items.
value; memory; selective encoding; reward; metacognitive control; functional magnetic resonance imaging (fMRI)
Examining the function of individual human hippocampal subfields remains challenging due to their small sizes and convoluted structures. Previous human functional magnetic resonance (fMRI) studies at 3 Tesla (T) have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, 3 and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution functional magnetic resonance imaging (fMRI) scanning at 7T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning, and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.
Hippocampus; memory; fMRI; MRI; high-resolution imaging
Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.
Entorhinal cortex; Hippocampus; Magnetic resonance imaging; Cortical unfolding; APOE-4 allele
Grid cells in the entorhinal cortex appear to represent spatial location via a triangular coordinate system. Such cells, which have been identified in rats, bats, and monkeys, are believed to support a wide range of spatial behaviors. By recording neuronal activity from neurosurgical patients performing a virtual-navigation task we identified cells exhibiting grid-like spiking patterns in the human brain, suggesting that humans and simpler animals rely on homologous spatial-coding schemes.
Patient studies have not provided consistent evidence for interictal neuronal hyperexcitability inside the seizure onset zone (SOZ). We hypothesized that gray matter (GM) loss could have important effects on neuronal firing, and quantifying these effects would reveal significant differences in neuronal firing inside versus outside the SOZ.
MRI and computational unfolding of mesial temporal lobe (MTL) subregions was used to construct anatomical maps to compute GM loss in presurgical patients with medically intractable focal seizures in relation to control subjects. In patients, these same maps were used to locate the position of microelectrodes that recorded interictal neuronal activity. Single neuron firing and burst rates were evaluated in relation to GM loss and MTL subregions inside and outside the SOZ.
MTL GM thickness was reduced inside and outside the SOZ in patients with respect to control subjects, yet GM loss was associated more strongly with firing and burst rates in several MTL subregions inside the SOZ. Adjusting single neuron firing and burst rates for the effects of GM loss revealed significantly higher firing rates in the subregion consisting of dentate gyrus and CA2 and CA3 (CA23DG), as well as CA1 and entorhinal cortex (EC) inside versus outside the SOZ where normalized MRI GM loss was ≥1.40 mm. Firing rates were higher in subicular cortex inside the SOZ at GM loss ≥1.97 mm, while burst rates were higher in CA23DG, CA1, and EC inside than outside the SOZ at similar levels of GM loss.
The correlation between GM loss and increased firing and burst rates suggests GM structural alterations in MTL subregions are associated with interictal neuronal hyperexcitability inside the SOZ. Significant differences in firing rates and bursting in areas with GM loss inside compared to outside the SOZ indicate that synaptic reorganization following cell loss could be associated with varying degrees of epileptogenicity in patients with intractable focal seizures.
epilepsy; atrophy; interictal; hippocampus; MRI; microelectrode; single neuron
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).
Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.
Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.)
Although the hippocampus is critical for the formation and retrieval of spatial memories, it is unclear how subregions are differentially involved in these processes. Previous high-resolution functional magnetic resonance imaging (fMRI) studies have shown that CA2, CA3, and dentate gyrus (CA23DG) regions support the encoding of novel associations, while the subicular cortices support the retrieval of these learned associations. Whether these subregions are employed in humans during encoding and retrieval of spatial information has yet to be explored. Using high-resolution fMRI (1.6 mm × 1.6 mm in-plane), we found that activity within the right CA23DG increased during encoding compared to retrieval. Conversely, right subicular activity increased during retrieval compared to encoding of spatial associations. These results are consistent with previous studies illustrating dissociations within human hippocampal subregions and further suggest these regions are similarly involved during the encoding and retrieval of spatial information.
hippocampus; CA3; subiculum; fMRI; encoding; retrieval; spatial learning
Neuroscience can be used as a tool to inspire an interest in science in school children as well as to provide teaching experience to college students.
Previous functional magnetic resonance imaging (MRI) studies in healthy subjects with the apolipoprotein E 4 (APOE-4) genetic risk for Alzheimer’s disease have shown increased activation during memory task performance in broadly distributed cortical regions. These findings have been hypothesized to reflect compensatory recruitment of intact brain regions that presumably result from subtle neural dysfunction reflecting incipient disease. In this study, we used high-resolution functional MRI in APOE-4 carriers and non-carriers to measure activity in hippocampal subregions (CA fields 1, 2, 3; dentate gyrus [DG], and subiculum) and adjacent medial temporal lobe (parahippocampal and entorhinal) subregions. We found reduced left CA2, 3 and dentate gyrus (CA23DG) activity in cognitively intact APOE-4 carriers. These results suggest that reduced neural activity in hippocampal subregions may underlie the compensatory increase in extra hippocampal activity in people with a genetic risk for Alzheimer’s disease prior to the onset of cognitive deficits.
Alzheimer’s Disease; ApoE; Hippocampus; MRI; fMRI; high-resolution imaging
People with the apolipoprotein-Eε4 (APOE-4) genetic risk for Alzheimer’s disease show morphologic differences in medial temporal lobe regions when compared to non-carriers of the allele. Using a high-resolution MRI and cortical unfolding approach, our aim was to determine the rate of cortical thinning among medial temporal lobe subregions over the course of 2 years. We hypothesized that APOE-4 genetic risk would contribute to longitudinal cortical thickness change in the subiculum and entorhinal cortex, regions preferentially susceptible to Alzheimer’s disease related pathology. Thirty-two cognitively intact subjects, mean age 61 years, 16 APOE-4 carriers, 16 non-carriers, underwent baseline and follow-up MRI scans. Over this relatively brief interval, we found significantly greater cortical thinning in the subiculum and entorhinal cortex of APOE-4 carriers when compared to non-carriers of the allele. Average cortical thinning across all medial temporal lobe subregions combined was also significantly greater for APOE-4 carriers. This finding is consistent with the hypothesis that carrying the APOE-4 allele renders subjects at a higher risk for developing Alzheimer’s disease.
Alzheimer’s disease; APOE genotype; High-resolution MRI; Medial temporal lobe; Cortical unfolding; Cortical thickness
Structural brain changes appear years before the onset of Alzheimer’s disease, the leading cause of dementia late in life. Determining risk factors for such presymptomatic brain changes may assist in identifying candidates for future prevention treatment trials. In addition to the e4 allele of the apolipoprotein E gene (APOE-4), the major known genetic risk factor, a family history of Alzheimer’s disease also increases the risk to develop the disease, reflecting yet unidentified genetic and, perhaps, nongenetic risks. The authors investigated the influence of APOE-4 genotype and family history risks on cortical thickness in medial temporal lobe subregions among volunteers without cognitive impairment.
High-resolution magnetic resonance imaging (MRI) and a cortical unfolding method were performed on 26 subjects (APOE-4 carriers: N =13; noncarriers: N =13) with at least one first-degree relative with Alzheimer’s disease and 25 subjects (APOE-4 carriers: N =12; noncarriers: N =13) without this risk factor. All subjects (mean age: 62.3 years [SD=10.7]; range=38–86 years) were cognitively healthy.
Family history of Alzheimer’s disease and APOE-4 status were associated with a thinner cortex in the entorhinal region, subiculum, and adjacent medial temporal lobe subfields. Although these associations were additive, family history of Alzheimer’s disease explained a greater proportion of the unique variance in cortical thickness than APOE-4 carrier status.
APOE-4 carrier status and family history of Alzheimer’s disease are independently associated with and contribute additively to hippocampal cortical thinning.
The hippocampus is often a difficult structure to visualize with magnetic resonance imaging (MRI) and functional MRI (fMRI) due to its convoluted nature and susceptibility to signal dropout. Improving our ability to pinpoint changes in neural activity using fMRI in this structure remains an important challenge. Current fMRI/MRI methods typically do not permit visualization of the hippocampus and surrounding cortex at a resolution less than one mm. We present here improvements to our previous methods for obtaining structural MR images of the hippocampus, which provided an in-plane resolution of 0.4 mm2 mm and two-dimensional “flat” maps of the hippocampus with an interpolated isotropic resolution of 0.4mm3 (Engel et al., 1997; Zeineh et al., 2000). We present changes to existing structural imaging sequences that now augment the resolution of previous scans, permitting visualization of the anterior portion of CA1, parts of the dentate gyrus, and CA23. These imaging improvements are of relevance generally to the field of imaging because they permit higher overall resolution imaging of the hippocampus than previously possible (at 3 Tesla). We also introduce a novel application of a computational interpolation method that improves our ability to capture the convoluted three-dimensional shape of the hippocampus. Furthermore, we have developed a quantitative method for obtaining group activation patterns based on producing averaged flat maps using vector field warping techniques, allowing localization of activations to specific hippocampal subregions across groups of subjects. Together, these methods provide a means to improve imaging of neural activity in the human hippocampus and surrounding cortex during cognitive tasks.
Hippocampus; MRI; fMRI; high-resolution imaging
A central component of our ability to navigate an environment is the formation of a memory representation that is allocentric and thus independent of our starting point within that environment. Computational models and rodent electrophysiological recordings suggest a critical role for the CA1 subregion of the hippocampus in this type of coding; however, the hippocampal neural basis of spatial learning in humans remains unclear. We studied subjects learning virtual environments using high-resolution functional magnetic resonance imaging (1.6 mm × 1.6 mm in-plane) and computational unfolding to better visualize substructural changes in neural activity in the hippocampus. We show that the right posterior CA1 subregion is active and positively correlated with performance when subjects learn a spatial environment independent of starting point and direction. Altogether, our results demonstrate that the CA1 subregion is involved in our ability to learn a map-like representation of an environment.
Localization and targeting of depth electrodes in specific regions of the human brain is critical for accurate clinical diagnoses and treatment as well as for neuroscientific electrophysiological research. By using high-resolution magnetic resonance imaging combined with 2D computational unfolding, the authors present a method that improves electrode localization in the medial temporal lobe. This method permits visualization of electrode placements in subregions of the hippocampus and parahippocampal gyrus, allowing for greater specificity in relating electrophysiological and anatomical features in the human medial temporal lobe. Such methods may be extended to therapeutic procedures targeting specific neuronal circuitry in subfields of structures deep in the human brain.
coregistration; depth electrode; electrode localization; epilepsy; hippocampus
The goal of this study is to investigate the effect of the hormone melatonin on long-term potentiation and excitability measured by stimulating the Schaffer collaterals and recording the field excitatory postsynaptic potential from the CA1 dendritic layer in hippocampal brain slices from mice. Application of melatonin produced a concentration-dependent inhibition of the induction of long-term potentiation, with a concentration of 100 nM producing an ≈50% inhibition of long-term potentiation magnitude. Long-duration melatonin treatments of 6 h were also effective at reducing the magnitude of long-term potentiation. Melatonin (100 nM) did not alter baseline evoked responses or paired-pulse facilitation recorded at this synapse. The inhibitory actions of melatonin were prevented by application of the melatonin (MT) receptor antagonist luzindole as well as the MT2 receptor subtype antagonist 4-phenyl-2-propionamidotetraline. These inhibitory actions of melatonin were lost in mice deficient in MT2 receptors but not those deficient in MT1 receptors. In addition, application of the protein kinase A inhibitor H-89 both mimicked the effects of melatonin and precluded further inhibition by melatonin. Finally, the application an activator of adenylyl cyclase, forskolin, overcame the inhibitory effects of melatonin on LTP without affecting the induction of long-term potentiation on its own. These results suggest that hippocampal synaptic plasticity may be constrained by melatonin through a mechanism involving MT2-receptor-mediated regulation of the adenylyl cyclase–protein kinase A pathway.
hippocampus; LTP; melatonin; mice; synaptic plasticity