**2. Task-specific connectivity of the hippocampus**

### **2.1 Connectivity with sensorimotor regions during movement tasks**

Known hippocampal properties of memory or navigation are not required by common daily movements, such as walking or even "automatic driving" behaviors, so few human studies have examined hippocampal connectivity with motor regions. Initially, those that did examined hippocampal connectivity during sequence learning [44–46], where subjects learn an unfamiliar pattern of finger movements. Hippocampal connectivity was observed with the striatum, suggesting a mnemonic-motor interaction [46], perhaps culminating in striatal-associated movements derived from habits [47, 48].

Hippocampal connectivity with sensorimotor cortex (SMC) was recently studied with PPI during two paced motor tasks, only one of which involved motor learning [49]. For both tasks, subjects were instructed to listen to a 2 Hz metronome for 2 s before initiating movements, then tap the appropriate finger in synchrony with the taps from a metronome. Subjects quickly anticipated the timing of the taps, moving shortly before the sound; thus, cognitive awareness of the expected timing informed motor behavior. During the sequence learning task, the temporal precision and variability of right-handed finger movements improved with repetition; no such learning effects were observed in the repetitive tapping task.

Sensorimotor cortical activation during these tasks (**Figure 1A**) was consistent with previous studies. The sequence learning task was performed with the right hand only, evoking focal activation in left sensorimotor cortex, both in pre- and postcentral gyrus; repetitive tapping was performed with both hands, evoking bilateral sensorimotor activation. Although positive connectivity during sequence

### **Figure 1.**

*Sensorimotor activation during performance of motor tasks. (A) Group analysis revealed unilateral activation in left sensorimotor cortex during performance of the unimanual sequence learning task and bilateral activation during the bimanual repetitive tapping task. (B) Inverse connectivity was generated from three structural seeds in both tasks, evident in the left sensorimotor cortex during sequential learning and the right sensorimotor cortex during repetitive tapping. The extent of connectivity was larger using combined ("bilateral") activity from corresponding regions of the left and right hippocampus (bottom). Images are shown in the neurological format (left side of axial images represents left side of brain); structural and functional seeds refer to the method of selecting hippocampal seed regions for connectivity analysis, as described elsewhere [49].*

*Hippocampal Influences on Movements, Sensory, and Language Processing: A Role in Cognitive… DOI: http://dx.doi.org/10.5772/intechopen.100122*

learning was also observed from localized hippocampal regions, inverse (negative) connectivity was more prevalent. During sequence learning, inverse connectivity from central and central-medial regions of the left hippocampus was observed in left SMC (**Figure 1B**, left); the volume of connectivity was slightly improved when examining joint connectivity from the hippocampus in both hemispheres. Inverse connectivity from anterior middle and lateral regions of the hippocampus was observed during repetitive tapping in the right SMC, most evident examining joint connectivity from the hippocampus in both hemispheres (**Figure 1B**, right).

During both tasks, hippocampal connectivity selectively targeted the hand representation within SMC, overlapping the region activated by the task.

### **2.2 Connectivity with sensory regions during sensory tasks**

Sensory information passes into the brain passively through bottom-up processes, but can be enhanced or filtered through top-down processes [50–53]. Top-down processes modify neural responses based on expectations or attentional processes.

Hippocampal influences on cortical processes were examined on tasks that enhanced sensory activation. The Stroop task requires particular attention to colors. On separate trials, words that name colors and cross symbols were presented in colored inks. The word meaning may or may not represent the same color as the ink in which it is written, but the correct behavioral response depends on the ink color. Due to interference from the automatic recognition of the word meaning, subjects require extra time to respond on word trials, especially on mismatch trials; to respond correctly, they must attend to the stimulus color while suppressing the behavioral response suggested by the word meaning. Activation by colored words (vs. colored crosses) was observed in the left inferior frontal gyrus and ventrolateral visual cortex (see **Figure 2A**). Within the activated region, a ventrolateral visual cortex specialized for color [54, 55] showed inverse connectivity from the hippocampus (**Figure 2B**). Despite activation in the left inferior frontal gyrus, an area involved in language function, no hippocampal connectivity was observed there.

Images and sounds that evoke a strong emotional response evoke strong activation in sensory cortices. **Figure 3** shows activation and connectivity associated with a task where subjects were instructed to pay attention to music and images, allowing an emotional response to what they viewed. Pictures were presented from a national database where thousands of subjects had rated images for the intensity and sign of their affective response [56]; harsh dissonant music accompanied negative images, upbeat classical music accompanied positive images, and bland jazz music accompanied neutral images, interspersed between positive and negative images. **Figure 3** shows brain activity evoked by negative stimuli. **Figure 3A** shows bilateral activation in visual cortex along the calcarine sulcus, plus auditory association cortex within the superior temporal gyrus; a similar pattern of activation was observed for positive stimuli (not shown). Hippocampal connectivity was not observed in visual cortex, whereas inverse connectivity was observed bilaterally in the activated region of the superior temporal gyrus (**Figure 3B**).

Tactile brain activation was tested by rubbing the arms of thirty-five patients with brain tumors evaluated during pre-operative planning. Patients were instructed to attend to the spatial pattern of tactile stimuli, which were applied bilaterally; analysis was carried out separately for those patients with tactile impairments on the left vs. right sides. Bilateral activation was generated in the postcentral gyrus, weaker in the sensory cortex contralateral to the sensory deficit (not shown). Hippocampal connectivity was absent.

### **Figure 2.**

*Activation and hippocampal connectivity during performance of Stroop task. (A) Activation was observed in the left inferior frontal gyrus (a language area), the left inferior parietal lobe, and bilateral occipital cortex, extending into the fusiform gyrus (visual areas). (B) Inverse connectivity from bilateral seeds in the center of the hippocampus was observed in fusiform regions associated with color processing.*

As illustrated above, hippocampal connectivity was never observed in a primary sensory region, but was observed in activated regions of sensory association cortex (for example, the activated color association cortex during the Stroop task and auditory association cortex during dissonant music). This pattern of results has functional implications. Patterns of visual cortex activity are constrained by attentional processes and cognitive expectations [57], and the hippocampal mechanism of pattern completion reflects cognitive expectations [58]. Visual responses in the hippocampus are retinotopic, suggesting their joint function in sensations and memory [59]. Visual and auditory areas specialized for language also receive hippocampal input (as shown in the next section). This pattern of results suggests consistent hippocampal cognitive input to sensory areas that extract features relevant to task performance.

*Hippocampal Influences on Movements, Sensory, and Language Processing: A Role in Cognitive… DOI: http://dx.doi.org/10.5772/intechopen.100122*

### **Figure 3.**

*Activation and hippocampal connectivity during presentation of multisensory emotionally-charged stimuli. (A) Activation was observed bilaterally in the occipital cortex along the calcarine gyrus and the superior temporal gyrus. Emotionally-charged photographic images accompanied by dissonant music were contrasted with neutral images of furniture, faces, and scenery. (B) Hippocampal connectivity was limited to auditory association cortex within the superior temporal gyrus.*

### **2.3 Connectivity with language regions during language tasks**

The language network consists of interconnected brain regions that vary in linguistic properties. The left inferior frontal gyrus (Broca's area) is typically active during all language tasks, although subregions have been identified with various linguistic functions [60, 61]. Occipital and temporal regions are specialized for processing specific linguistic components [62–67]. The default mode network typically shows decreased activity during language judgment tasks, yet the magnitude of its activation and connectivity with language areas can be correlated with performance accuracy [68, 69].

Representative activity during three language tasks is shown in **Figure 4**. **Figure 4A** shows results from both a t-test analysis (representing positive activation, yellow) and an anova F-test (red); overlap appears in orange. The t-test analysis shows the traditional language network, including the left inferior frontal gyrus, middle and adjacent superior temporal gyrus, and the fusiform gyrus. The F-test analysis additionally shows deactivation in the default mode network, including the precuneus, angular gyrus, and ventromedial prefrontal cortex. Regions with hippocampal connectivity during the auditory version of these tasks is shown in **Figure 4B**, both for adults (yellow) and children (red). In the orthography task, *inverse* connectivity was observed for children in the left fusiform gyrus and the posterior default mode network; all other regions reflect *positive* connectivity. A larger area of connectivity was observed in adults for phonology

### **Figure 4.**

*Activation and hippocampal connectivity during language tasks. (A) Activation during language tasks was evaluated both with an F-test (red) and t-test (yellow). Areas identified from the t-test are traditionally associated with language activation, including the left inferior frontal gyrus, middle/superior temporal gyrus, and fusiform gyrus; the F-test additionally demonstrated areas in the default mode network (precuneus, angular gyrus, and ventromedial prefrontal cortex). (B) Hippocampal connectivity varied across different language tasks. During the orthography task, hippocampal connectivity in the fusiform gyrus was more anterior in children than adults, who also showed connectivity in the angular gyrus. Hippocampal connectivity in the phonology and semantic tasks overlapped in the temporal gyrus, extending further posterior during semantics; the semantics task additionally showed connectivity in the left inferior frontal gyrus and ventromedial prefrontal cortex.*

*Hippocampal Influences on Movements, Sensory, and Language Processing: A Role in Cognitive… DOI: http://dx.doi.org/10.5772/intechopen.100122*

and semantic tasks, encompassing the area of connectivity observed in children. In addition, adults showed connectivity in the left insula/inferior frontal gyrus (Broca's area) in the semantics task, as well as ventromedial prefrontal cortex of the default mode network.

These three language tasks varied only in the linguistic judgment required for accurate performance [70, 71]. Three words were presented sequentially; the required response depended on the rule designated for that task (the third word must be spelled the same, rhyme, or be related in meaning to either of the two previous words). Hippocampal activity likely reflected its memory for the first two words, consistent with its mnemonic function, yet its connectivity with language areas depended on the task requirements. The three language tasks preferentially activated different areas in the language network (**Figure 5A**): fusiform gyrus

### **Figure 5.**

*Language task selectivity and developmental changes in hippocampal connectivity. (A) Task-preferential activation was observed in the left fusiform gyrus (orthography), posterior middle/superior temporal gyrus (semantics), and adjacent superior temporal gyrus (phonology). (B) Hippocampal connectivity showed the same task-dependent pattern. (C) Developmental increases in hippocampal connectivity were observed in most language areas (left fusiform, posterior middle/superior temporal gyrus, inferior frontal gyrus), plus part of the default mode network (precuneus, angular gyrus). Different regions of the hippocampus showed developmental increases with different cortical areas.*

for orthography, superior temporal gyrus for phonology, and posterior middle temporal gyrus for semantics. These same areas showed task-specific connectivity from the hippocampus (**Figure 5B**). Language deficits are associated with abnormal activity or connections in these areas [72, 73]; thus, hippocampal connectivity altered the activity in those language areas necessary for performing the task.

Hippocampal connectivity with language areas increased through adulthood, with different hippocampal regions showing developmental increases in connectivity with different cortical areas (**Figure 5C**). Areas with increased connectivity included the fusiform and posterior middle temporal regions (associated with spelling and semantics, respectively), but also the inferior frontal gyrus and parts of the default mode network. Developmental changes have also been observed within the language network, both in activation [71, 74–76] and connectivity [77–80]. Developmental changes have been tied to changes in language skills [81, 82]. Developmental changes in hippocampal connectivity may reflect cognitive changes associated with these language skills.

### **2.4 Connectivity with prefrontal regions during memory tasks**

Different types of memory are often differentiated by interactions between different brain regions. Many memories are believed to involve the hippocampus, either during memory formation, the search for a specific memory ("construction" for autobiographical memories), its elaboration during recall, or updating {"integrating") memories to incorporate new content.

In autobiographical memories, posterior hippocampal regions interact with visual perceptual areas [83, 84]; during the construction of these memories and imagined future events, anterior hippocampal regions show increased connectivity with prefrontal regions [83]. New information inconsistent with a previous schema changes hippocampal-prefrontal connectivity [85]. Successful integration of recalled information in an inference task results in enhanced hippocampal theta power, plus coherence in medial prefrontal cortex [86], suggesting a directional flow of information from the hippocampus to prefrontal areas. During a working memory task, hippocampal activity precedes frontal activity during successful trials [86], reflecting successful retrieval and suggesting a directional flow of information from the hippocampus to prefrontal cortex. In combined EEG-fMRI recordings, recollection-specific theta-alpha (4–13 Hz) effects are correlated with increases in hippocampal connectivity with the PFC and the striatum, areas that have been linked repeatedly to retrieval success [87, 88].

Information also flows in the reverse direction. Ventromedial prefrontal cortex drives the hippocampus during the generation and processing of mismatch signals; the hippocampus then integrates this information into a new schema, modifying existing memories [89]. Elaboration of emotional autobiographical memories generates connectivity from ventromedial prefrontal cortex to the hippocampus, with greater connectivity generated during highly emotionally arousing events than those with neutral or positive affect [83]. Prefrontal feedback may thus reinforce the strength of hippocampal activity based on emotional content, explaining why emotionally-charged events are more likely to be remembered [90, 91]. Bidirectional interactions between the hippocampus and medial prefrontal cortex also play a role in working, episodic, and spatial memory [92, 93], with dysfunction in these pathways likely contributing to psychiatric disorders [94, 95]. The pattern of information flow suggests that the context of ongoing experience (the schema) is required to retrieve relevant memories, allowing patterns of neural activity from the original event to be recreated in sensory association cortices [96, 97].

*Hippocampal Influences on Movements, Sensory, and Language Processing: A Role in Cognitive… DOI: http://dx.doi.org/10.5772/intechopen.100122*

In summary, the flow of information between the hippocampus and prefrontal cortex is bidirectional during memory-related tasks: the hippocampus provides contextual information when novel stimuli or patterns appear, with feedback from the prefrontal cortex resetting the contextual schema in perceptual areas that provide input to the hippocampus.
