Parahippocampal gyrus

The parahippocampal gyrus is a prominent cortical structure located on the medial aspect of the temporal lobe in the human brain, forming a key component of the limbic system and lying adjacent to the hippocampus on the medial temporal lobe.^[1] It appears as an inrolled gyrus on the inferior surface of the temporal lobe, bordered anteriorly by the rhinal sulcus and uncus, and separated from the hippocampus by the subiculum and uncal sulcus.^[1] This gyrus encompasses the entorhinal cortex along its length and is continuous with the cingulate gyrus superiorly, contributing to the ring-like configuration of the limbic lobe.^[1] Functionally, the parahippocampal gyrus plays a central role in cognitive processes, particularly episodic memory formation and retrieval, by facilitating the binding of contextual information with specific items or events.^[2] It integrates spatial and non-spatial contextual associations, supporting tasks such as scene recognition and visuospatial navigation, with its posterior portion—known as the parahippocampal place area (PPA)—specializing in processing environmental layouts and landmarks.^[2] The gyrus receives inputs from visual areas like V4, the superior temporal gyrus, and the retrosplenial cortex, while projecting to the hippocampus, amygdala, and prefrontal cortex, thereby linking sensory processing with emotional and mnemonic functions.^[2] In relation to memory networks, the parahippocampal gyrus serves as a gateway for information flow to the hippocampus, essential for the consolidation of declarative memories, and bilateral lesions in this region can severely impair short-term and long-term memory capabilities.^[3] Its involvement extends to associative learning, where it helps encode relationships between stimuli and their contexts, underscoring its broader significance in higher-order cognition beyond isolated sensory processing.^[2]

Anatomy

Location

The parahippocampal gyrus is a grey matter cortical region that forms the medial border of the temporal lobe, wrapping around the inferior aspect of the hippocampus.^[1] It lies along the ventromedial edge of the temporal lobe and is positioned superior to the tentorium cerebelli.^[4] As a key component of the limbic system, it contributes to the medial temporal lobe's architecture.^[3] The structure extends anteriorly from near the temporal pole, where it curves medially to form the uncus, and posteriorly toward the occipital lobe, tapering at the isthmus of the cingulate gyrus.^[5] Laterally, it is bounded by the collateral sulcus, which separates it from the fusiform gyrus; medially, it is adjacent to the hippocampus and dentate gyrus, separated by the hippocampal sulcus.^[1]^[6]^[7] In healthy adults, the parahippocampal gyrus exhibits slight volumetric differences between the left and right hemispheres, with the left often larger.^[8] These asymmetries are subtle and vary across individuals but are consistent in neuroimaging studies of normal brain anatomy.^[9] On magnetic resonance imaging (MRI), the parahippocampal gyrus is visualized as a curved, C-shaped gyrus on sagittal slices, appearing continuous with the entorhinal cortex anteriorly.^[10] This imaging profile highlights its medial temporal position and aids in delineating its boundaries relative to adjacent structures.^[3]

Structure and subregions

The parahippocampal gyrus consists of allocortical and neocortical components, characterized by a transitional cytoarchitecture that bridges primitive and more advanced cortical layers. It encompasses several Brodmann areas, including area 27 (presubiculum), area 28 (ventral entorhinal cortex), area 35 (perirhinal cortex), and area 36 (parahippocampal proper or ectorhinal cortex).^[11]^[12] The gyrus is subdivided into anterior and posterior portions with distinct structural features. The anterior parahippocampal gyrus incorporates the perirhinal cortex (Brodmann area 35), located lateral to the entorhinal cortex on the medial bank of the collateral sulcus, and the entorhinal cortex (Brodmann areas 28 and 34), which forms the anteromedial aspect adjacent to the subiculum. The posterior parahippocampal gyrus includes the parahippocampal place area (PPA), a region situated at the junction of the collateral sulcus and parahippocampal surface, extending into the lingual and fusiform gyri. Additional cytoarchitectonic subdivisions in the caudal region include Ph1, Ph2, and Ph3 on the parahippocampal gyrus surface and medial collateral sulcus bank, each defined by variations in layer thickness and cell density.^[11]^[13]^[6] Cytoarchitecturally, the parahippocampal gyrus exhibits a layered organization that transitions from paleocortex anteriorly to neocortex posteriorly. In the entorhinal cortex, layer II is prominent and contains large multipolar stellate cells interspersed with pyramidal neurons, contributing to its allocortical appearance. More caudal areas, such as Ph1–Ph3, show neocortical traits like a defined granular layer IV, with Ph1 featuring medium-sized pyramidal cells in layers III and VI, Ph2 displaying a broad layer II and blurred layer IV, and Ph3 characterized by compact layer II and horizontal striping from dense layers IV and VI.^[14]^[6] The vascular supply to the parahippocampal gyrus primarily arises from branches of the posterior cerebral artery, including the hippocampal, posteromedial choroidal, and inferior temporal arteries, which provide 2 to 10 parahippocampal vessels penetrating the region. This supply renders the gyrus vulnerable to ischemia, particularly in posterior cerebral artery territory infarcts that can lead to selective neuronal damage in the medial temporal lobe.^[15]^[16] Developmentally, the parahippocampal gyrus originates from the embryonic archicortex, a primitive cortical structure, becoming distinguishable alongside the hippocampal formation by weeks 8–9 of gestation. This early differentiation involves the outgrowth of the parahippocampal gyrus around the emerging hippocampal fissure, with further shaping through infolding and lamination by the second trimester.^[17]^[18]

Functions

Memory encoding and retrieval

The parahippocampal gyrus serves as a critical hub for contextual memory integration, receiving multimodal sensory inputs from various cortical regions and relaying processed information to the hippocampus primarily through the perforant path originating from the entorhinal cortex.^[19] This pathway, comprising axons from layers II and III of the entorhinal cortex, projects to the dentate gyrus, CA3, CA1, and subiculum, enabling the consolidation of diverse sensory experiences into coherent memory traces.^[19] By filtering and integrating these inputs, the parahippocampal gyrus facilitates the transformation of raw sensory data into contextually relevant representations essential for long-term storage.^[20] In episodic memory formation, the parahippocampal gyrus plays a pivotal role in encoding item-context associations, with its subregions exhibiting specialized functions. The perirhinal cortex, an anterior component, primarily handles object familiarity and recognition, supporting the encoding of individual item features independent of spatial context.^[21] In contrast, the entorhinal cortex contributes to spatial-temporal binding, integrating object details with their environmental and sequential contexts to form unified episodic representations.^[21] Lesion studies in nonhuman primates demonstrate deficits in delayed non-matching-to-sample tasks following damage to these areas, particularly impairing recognition memory for novel stimuli at longer delays, underscoring their necessity for associative encoding.^[22] Functional MRI evidence further reveals parahippocampal activation during successful memory recall tasks, with increased signal in the parahippocampal cortex correlating with the retrieval of contextual details in episodic recollection.^[23] The parahippocampal gyrus also interacts with hippocampal theta rhythms (4-12 Hz) to support memory consolidation, exhibiting synchronized oscillations that coordinate encoding and retrieval processes. Theta phase-locking between the entorhinal cortex and hippocampus enhances communication during learning, facilitating the transfer of information for stable memory formation.^[24] This synchronization diminishes over time as memories consolidate, reflecting a shift toward neocortical dependence.^[24] Early lesion studies, such as those by Brenda Milner in the 1950s on patient H.M., who underwent bilateral medial temporal lobe resection including parahippocampal regions, established links between such damage and profound anterograde amnesia, highlighting the structure's indispensable role in memory acquisition.^[25]

Visuospatial and scene processing

The parahippocampal place area (PPA), located in the posterior portion of the parahippocampal gyrus, exhibits selective neural responses to visual scenes such as rooms, landscapes, and buildings, as opposed to isolated objects or faces, as demonstrated in functional magnetic resonance imaging (fMRI) studies.^[26] This region, first identified in the late 1990s, shows heightened activation when participants view complex spatial layouts, reflecting its role in processing the overall configuration or "gist" of environments.^[27] The PPA's selectivity is viewpoint-dependent, with stronger responses to scenes from novel perspectives, aiding in the rapid extraction of spatial structure.^[27] In visuospatial processing, the PPA contributes to topographic memory and navigation by integrating visual landmarks for route planning and orientation.^[28] During virtual reality tasks, where individuals navigate simulated environments using extra-maze cues, the PPA activates alongside other regions to encode the spatial significance of landmarks, such as their positions relative to paths.^[28] This supports efficient wayfinding without requiring explicit recall of episodic details, emphasizing its perceptual function in real-time spatial analysis.^[29] Unlike the hippocampus, which constructs flexible cognitive maps for long-term spatial navigation, the PPA primarily handles the initial extraction of scene gist from visual input, providing a foundational representation for higher-level mapping. This distinction is evident in fMRI paradigms where PPA responses persist for scene perception alone, while hippocampal engagement increases with memory demands like route learning. Lesions to the parahippocampal gyrus, particularly on the right side, can result in topographical disorientation, characterized by an inability to recognize familiar landmarks or navigate known environments, yet sparing general episodic memory.^[30] Patients with such damage often report getting lost in previously familiar places due to impaired scene recognition, without deficits in object identification or global amnesia.^[31] Recent ultra-high-field 7-tesla fMRI research has revealed fine-grained scene selectivity within the layers of the parahippocampal cortex, showing how immersive visual stimuli enhance representational specificity in the PPA for peripheral and layout details.^[32] The parahippocampal gyrus plays a key role in processing social cues embedded in contextual environments, particularly through activation in the right hemisphere during the detection of sarcasm and irony. In a study using voxel-based morphometry on patients with neurodegenerative diseases, poorer comprehension of sarcasm conveyed via paralinguistic cues, such as vocal tone and facial expressions, was associated with reduced gray matter volume in the bilateral posterior parahippocampal gyri, with specific involvement of the right parahippocampal region in integrating these contextual social signals to interpret ironic intent.^[33] This activation highlights the region's contribution to discerning subtle social nuances that rely on environmental and interpersonal context. In emotional scene processing, the parahippocampal gyrus enhances memory encoding for environments with affective valence, facilitating the integration of emotional significance into spatial representations. Functional neuroimaging during contextual fear conditioning tasks has shown that the parahippocampal gyrus, in concert with the amygdala, supports the formation of fear associations tied to specific locations, where amygdala inputs modulate parahippocampal activity to prioritize emotionally charged scenes for long-term retention.^[34] Similarly, amygdala-mediated enhancement of parahippocampal and hippocampal processing strengthens consolidation of negative emotional experiences during navigation, such as aversive spatial encounters, thereby improving recall of affectively valenced contexts.^[34] The parahippocampal gyrus also contributes to theory of mind by aiding inferences about others' intentions within scene-based social scenarios. During cognitive theory of mind tasks involving mental state attribution, activation in the parahippocampal gyrus, alongside regions like the temporoparietal junction, supports the contextual embedding of social interactions, allowing for the interpretation of intentions derived from environmental cues in interpersonal settings.^[35] Electrical stimulation studies further underscore this social processing role; direct stimulation of the parahippocampal place area induced vivid topographic visual hallucinations, including social elements such as perceiving investigators as workers in a pizza shop, suggesting the region's involvement in generating socially contextualized perceptual experiences.^[36] Connectivity between the parahippocampal gyrus and prefrontal cortex underpins social decision-making in emotionally navigated spaces. These pathways, including projections to the ventromedial and dorsolateral prefrontal cortices, enable context-dependent modulation of behavior, where parahippocampal representations of emotional environments inform prefrontal evaluations of social risks and rewards during navigation through interpersonal or affect-laden settings.^[37]

Clinical significance

Neurological disorders

The parahippocampal gyrus is frequently implicated in hippocampal sclerosis, a common pathological feature of mesial temporal lobe epilepsy (TLE), where atrophy extends beyond the hippocampus to include parahippocampal structures, contributing to seizure generation and propagation.^[38] In approximately 70% of TLE cases, mesial hippocampal sclerosis is present, often involving parahippocampal volume loss detectable on MRI, which correlates with disease duration and surgical outcomes.^[39] This atrophy disrupts normal memory encoding processes, leading to anterograde amnesia and resistance to antiepileptic drugs in affected patients.^[40] In Alzheimer's disease (AD), the entorhinal cortex—a key subregion of the parahippocampal gyrus—exhibits early tau pathology, which precedes amyloid-beta accumulation and initiates memory decline by impairing synaptic function in the medial temporal lobe.^[41] This tau buildup disrupts connectivity between the entorhinal cortex and hippocampus, resulting in episodic memory deficits as an initial clinical manifestation.^[42] Volumetric reductions in the entorhinal cortex, measurable via structural MRI, serve as an early biomarker for AD progression, with approximately 13% volume reduction observed in mild cognitive impairment (prodromal stage) compared to healthy controls.^[43] Lesions in the posterior parahippocampal gyrus are associated with topographical disorientation syndromes, particularly landmark agnosia, where patients fail to recognize familiar environmental landmarks despite intact basic visual perception.^[44] Damage to the right posterior parahippocampal region impairs the acquisition of novel spatial information about scenes and buildings, leading to difficulties in route navigation and egocentric orientation.^[45] This selective deficit highlights the region's role in integrating visuospatial cues for topographic memory, distinct from broader amnesia.^[46] Recent studies have identified altered functional connectivity involving the parahippocampal gyrus in the neural network underlying chronic tinnitus perception, where hyperactivity and disrupted limbic-auditory interactions perpetuate phantom sound awareness.^[47] These changes suggest the parahippocampal gyrus contributes to the emotional and memory-related amplification of tinnitus signals.^[48] Disrupted functional connectivity between the brainstem ascending reticular activating system and the left parahippocampal gyrus has emerged as a potential biomarker for delirium in patients with intracerebral hemorrhage, particularly following basal ganglia lesions.^[49] A 2025 study of hemorrhage patients demonstrated significantly lower z-scores for this connectivity in those with delirium versus non-delirium controls, with values effectively distinguishing the groups (AUC > 0.85) and linking to arousal dysregulation.^[50] This alteration may underlie the acute attentional and cognitive fluctuations characteristic of post-hemorrhage delirium.^[51]

Psychiatric disorders

In schizophrenia, structural alterations in the parahippocampal gyrus include reduced volumes and disrupted right-left asymmetry, which have been linked to core symptom profiles. Meta-analyses of MRI studies indicate that parahippocampal volume reductions are more pronounced in chronic cases, with asymmetry changes potentially reflecting early neurodevelopmental disruptions.^[52]^[53] These volumetric deficits correlate inversely with negative symptoms such as social withdrawal and blunted affect, suggesting impaired contextual processing in social environments.^[54] Additionally, altered temporal lobe asymmetries may contribute to misattribution of internal speech to external sources in auditory hallucinations.^[55] These findings highlight potential laminar-specific vulnerabilities in excitatory-inhibitory balance within the medial temporal lobe, which may underlie broader corticolimbic dysregulations. Functional connectivity analyses further delineate subtypes of schizophrenia based on medial temporal lobe patterns, where variations in parahippocampal connectivity to prefrontal and temporal regions predict symptom severity, including disorganized thinking and perceptual disturbances.^[56]^[57] In major depressive disorder and anxiety disorders, the parahippocampal gyrus exhibits hyperactivation during tasks involving emotional scene processing, such as viewing negative or ambiguous environments, which sustains maladaptive rumination.^[58] Meta-analyses of functional MRI data show increased medial temporal hyperactivity in response to emotionally salient stimuli, correlating with rumination tendencies that perpetuate depressive cycles.^[59] This hyperactivation may reflect impaired disengagement from threat-related contexts, exacerbating anxiety symptoms like excessive worry.^[60] In posttraumatic stress disorder (PTSD), enhanced functional coupling between the amygdala and parahippocampal gyrus during fear memory reconsolidation contributes to the persistence of trauma-related intrusions. Neuroimaging studies demonstrate strengthened amygdala-parahippocampal interactions when trauma cues trigger memory reactivation, leading to overgeneralization of fear responses.^[61]^[62] These connectivity alterations are associated with heightened symptom severity, including hyperarousal and avoidance behaviors. Across psychiatric disorders, subtype-specific variations in medial temporal lobe functional connectivity, encompassing the parahippocampal gyrus, further modulate overall symptom profiles, with hyperconnected patterns linked to more severe affective dysregulation.^[63]^[64]