Itamar Kahn

Parietal lobe contributions to episodic memory retrieval.

Although the parietal lobe is not traditionally thought to support declarative memory, recent event-related fMRI studies of episodic retrieval have consistently revealed a range of memory-related influences on activation in lateral posterior parietal cortex (PPC) and precuneus extending into posterior cingulate and retrosplenial cortex. This article surveys the fMRI literature on PPC activation during remembering, a literature that complements earlier electroencephalography data. We consider these recent memory-related fMRI responses within the context of classical ideas about parietal function that emphasize space-based attention and motor intention. We conclude by proposing three hypotheses concerning how parietal cortex might contribute to memory.

Evidence for a Frontoparietal Control System Revealed by Intrinsic Functional Connectivity

Two functionally distinct, and potentially competing, brain networks have been recently identified that can be broadly distinguished by their contrasting roles in attention to the external world versus internally directed mentation involving long-term memory. At the core of these two networks are the dorsal attention system and the hippocampal-cortical memory system, a component of the brains default network. Here spontaneous blood-oxygenation-level-dependent (BOLD) signal correlations were used in three separate functional magnetic resonance imaging data sets (n = 105) to define a third system, the frontoparietal control system, which is spatially interposed between these two previously defined systems. The frontoparietal control system includes many regions identified as supporting cognitive control and decision-making processes including lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Detailed analysis of frontal and parietal cortex, including use of high-resolution data, revealed clear evidence for contiguous but distinct regions: in general, the regions associated with the frontoparietal control system are situated between components of the dorsal attention and hippocampal-cortical memory systems. The frontoparietal control system is therefore anatomically positioned to integrate information from these two opposing brain systems.

Functional-Neuroanatomic Correlates of Recollection: Implications for Models of Recognition Memory

Recognition decisions can be based on familiarity, the sense that an item was encountered previously (item memory), and on recollection, the conscious recovery of contextual information surrounding a previous encounter with the item (e.g., source memory). Recognition with recollection is thought to depend on multiple mechanisms, including prefrontal “control” processes that guide retrieval and recapitulation mechanisms that reactivate posterior neocortical representations that were present at encoding. However, uncertainty remains regarding the precise nature of prefrontal contributions to recollection and the selectivity of recapitulation to veridical recollection. The present event-related functional magnetic resonance imaging study sought to examine whether regions showing “old-new” effects support processes sensitive to recollection success or recollection attempt and whether recapitulation of neocortical representations emerge during veridical recollection as well as during false recognition (i.e., false alarms) or whether false recognition resembles familiarity-based responding. Results revealed that multiple left prefrontal cortical regions were engaged during attempts to recollect previous contextual (source) details, regardless of the nature of the to-be-recollected details and of source recollection outcome (successful vs unsuccessful). Recapitulation effects were observed in regions sensitive to the encoding task, suggesting that veridical recollection entails the reactivation of processes or representations present during encoding. Importantly, in contrast to leading models of recognition memory, false alarms also appeared to be based partially on recollection, as revealed through false recapitulation effects. Implications for neural and cognitive models of recognition are considered.

Distinct Cortical Anatomy Linked to Subregions of the Medial Temporal Lobe Revealed by Intrinsic Functional Connectivity

The hippocampus and adjacent cortical structures in the medial temporal lobe (MTL) contribute to memory through interactions with distributed brain areas. Studies of monkey and rodent anatomy suggest that parallel pathways converge on distinct subregions of the MTL. To explore the cortical areas linked to subregions of the MTL in humans, we examined cortico-cortical and hippocampal-cortical correlations using high-resolution, functional connectivity analysis in 100 individuals. MTL seed regions extended along the anterior to posterior axis and included hippocampus and adjacent structures. Results revealed two separate brain pathways that correlated with distinct subregions within the MTL. The body of the hippocampus and posterior parahippocampal cortex correlated with lateral parietal cortex, regions along the posterior midline including posterior cingulate and retrosplenial cortex, and ventral medial prefrontal cortex. By contrast, anterior hippocampus and the perirhinal/entorhinal cortices correlated with distinct regions in the lateral temporal cortex extending into the temporal pole. The present results are largely consistent with known connectivity in the monkey and provide a novel task-independent dissociation of the parallel pathways supporting the MTL memory system in humans. The cortical pathways include regions that have undergone considerable areal expansion in humans, providing insight into how the MTL memory system has evolved to support a diverse array of cognitive domains.

Memory Strength and Repetition Suppression: Multimodal Imaging of Medial Temporal Cortical Contributions to Recognition

Declarative memory permits an organism to recognize stimuli that have been previously encountered, discriminating them from those that are novel. One basis for recognition is item memory strength, which may support the perception of stimulus familiarity. Though the medial temporal lobes are known to be critical for declarative memory, at present the neural mechanisms supporting perceived differences in memory strength remain poorly specified. Here, functional MRI (fMRI) and anatomically constrained magnetoencephalography (MEG) indexed correlates of graded memory strength in the human brain, focusing on medial temporal cortex. fMRI revealed a decrease in medial temporal cortical activation that tracked parametric levels of perceived memory strength. Anatomically constrained MEG current estimates revealed that strength-dependent signal reductions onset within 150-300 ms. Memory strength appears to be rapidly signaled by medial temporal cortex through repetition suppression (activation reductions), providing a basis for the subjective perception of stimulus familiarity or novelty.

The Neural Reality of Syntactic Transformations Evidence From Functional Magnetic Resonance Imaging

The functional anatomy of syntactic transformations, a major computational operation invoked in sentence processing, was identified through a functional magnetic resonance imaging investigation. A grammaticality judgment task was used, presented through a novel hidden-blocks design. Subjects listened to transformational and non-transformational sentences in which a host of other complexity generators (number of words, prepositions, embeddings, etc.) were kept constant. A series of analyses revealed that the neural processing of transformations is localizable, evoking a highly lateralized and localized activation in the left inferior frontal gyrus (Brocas region) and bilateral activation in the posterior superior temporal sulcus. The pattern of activation associated with transformational analysis was distinct from the one observed in neighboring regions, and anatomically separable from the effects of verb complexity, which yielded significant activation in the left posterior superior temporal sulcus. Taken together with neuropsychological evidence, these results uncover the neural reality of syntactic transformations.

Mapping Brain Networks in Awake Mice Using Combined Optical Neural Control and fMRI

Behaviors and brain disorders involve neural circuits that are widely distributed in the brain. The ability to map the functional connectivity of distributed circuits, and to assess how this connectivity evolves over time, will be facilitated by methods for characterizing the network impact of activating a specific subcircuit, cell type, or projection pathway. We describe here an approach using high-resolution blood oxygenation level-dependent (BOLD) functional MRI (fMRI) of the awake mouse brain-to measure the distributed BOLD response evoked by optical activation of a local, defined cell class expressing the light-gated ion channel channelrhodopsin-2 (ChR2). The utility of this opto-fMRI approach was explored by identifying known cortical and subcortical targets of pyramidal cells of the primary somatosensory cortex (SI) and by analyzing how the set of regions recruited by optogenetically driven SI activity differs between the awake and anesthetized states. Results showed positive BOLD responses in a distributed network that included secondary somatosensory cortex (SII), primary motor cortex (MI), caudoputamen (CP), and contralateral SI (c-SI). Measures in awake compared with anesthetized mice (0.7% isoflurane) showed significantly increased BOLD response in the local region (SI) and indirectly stimulated regions (SII, MI, CP, and c-SI), as well as increased BOLD signal temporal correlations between pairs of regions. These collective results suggest opto-fMRI can provide a controlled means for characterizing the distributed network downstream of a defined cell class in the awake brain. Opto-fMRI may find use in examining causal links between defined circuit elements in diverse behaviors and pathologies.

Characterization of the Functional MRI Response Temporal Linearity via Optical Control of Neocortical Pyramidal Neurons

The blood oxygenation level-dependent (BOLD) signal serves as the basis for human functional MRI (fMRI). Knowledge of the properties of the BOLD signal, such as how linear its response is to sensory stimuli, is essential for the design and interpretation of fMRI experiments. Here, we combined the cell-type and site-specific causal control provided by optogenetics and fMRI (opto-fMRI) in mice to test the linearity of BOLD signals driven by locally induced excitatory activity. We employed high-resolution mouse fMRI at 9.4 tesla to measure the BOLD response, and extracellular electrophysiological recordings to measure the effects of stimulation on single unit, multiunit, and local field potential activity. Optically driven stimulation of layer V neocortical pyramidal neurons resulted in a positive local BOLD response at the stimulated site. Consistent with a linear transform model, this locally driven BOLD response summated in response to closely spaced trains of stimulation. These properties were equivalent to responses generated through the multisynaptic method of driving neocortical activity by tactile sensory stimulation, and paralleled changes in electrophysiological measures. These results illustrate the potential of the opto-fMRI method and reinforce the critical assumption of human functional neuroimaging that—to first approximation—the BOLD response tracks local neural activity levels.

Intrinsic connectivity between the hippocampus, nucleus accumbens, and ventral tegmental area in humans

Recent studies suggest that memory formation in the hippocampus is modulated by the motivational significance of events, allowing past experience to adaptively guide behavior. The effects of motivation on memory are thought to depend on interactions between the hippocampus, the ventral tegmental area (VTA), and the nucleus accumbens (NAcc). Indeed, animal studies reveal anatomical pathways for circuit‐level interaction between these regions. However, a homologue circuit connectivity in humans remains to be shown. We characterized this circuitry in humans by exploiting spontaneous low‐frequency modulations in the fMRI signal (termed resting‐state functional connectivity), which are thought to reflect functionally related regions and their organization into functional networks in the brain. We examined connectivity in this network across two datasets (hi‐resolution, n = 100; standard resolution, n = 894). Results reveal convergent connectivity between the hippocampus, and both the NAcc and the VTA centered on ventral regions in the body of the hippocampus. Additionally, we found individual differences in the strength of connectivity within this network. Together, these results provide a novel task‐independent characterization of circuitry underlying interactions between the hippocampus, NAcc, and VTA and provide a framework with which to understand how connectivity might reflect and constrain the effects of motivation on memory.

Optogenetic drive of neocortical pyramidal neurons generates fMRI signals that are correlated with spiking activity.

Local fluctuations in the blood oxygenation level-dependent (BOLD) signal serve as the basis of functional magnetic resonance imaging (fMRI). Understanding the correlation between distinct aspects of neural activity and the BOLD response is fundamental to the interpretation of this widely used mapping signal. Analysis of this question requires the ability to precisely manipulate the activity of defined neurons. To achieve such control, we combined optogenetic drive of neocortical neurons with high-resolution (9.4 T) rodent fMRI and detailed analysis of neurophysiological data. Light-driven activation of pyramidal neurons resulted in a positive BOLD response at the stimulated site. To help differentiate the neurophysiological correlate(s) of the BOLD response, we employed light trains of the same average frequency, but with periodic and Poisson distributed pulse times. These different types of pulse trains generated dissociable patterns of single-unit, multi-unit and local field potential (LFP) activity, and of BOLD signals. The BOLD activity exhibited the strongest correlation to spiking activity with increasing rates of stimulation, and, to a first approximation, was linear with pulse delivery rate, while LFP activity showed a weaker correlation. These data provide an example of a strong correlation between spike rate and the BOLD response. This article is part of a Special Issue entitled Optogenetics (7th BRES).