Schizophrenia

### Abstract

Schizophrenia remains a puzzling psychiatric disorder, often explored through disparate frameworks—be they genetic, environmental, or neurological. This article investigates the multifaceted functions of various cerebral regions, including the septo-hippocampal complex, the temporo-parietal junction, the septal area, medial prefrontal cortex (mPFC), frontal and parietal lobes. Particularly, the Medial Temporoparietal Junction (TPJm) plays a critical role in the genesis and symptoms of schizophrenia. Using a unique patient case as an exemplar, this paper suggests that these traditionally correlational variables merit reevaluation as potential causal factors in this disorder.

### Introduction

Despite intensive research, schizophrenia remains an elusive enigma. Theories are manifold, linking its onset to a variety of factors—from genetics and environmental conditions to intricate neurological interplay. Aberrations in midline brain structures have been demonstrated to induce atypical behavior in adults. Areas proven to be irregular in individuals with schizophrenia include the pituitary gland, temporo-parietal junction, medial prefrontal cortex (mPFC), frontal and parietal lobes. Among these, the TPJm serves as a hub for social cognition and sensory integration. Through the perspective of a singular but compelling patient case, this article aims to transition these factors from merely correlational to potentially causal.

### The Patient

The patient's neurological landscape offers a complex tapestry of anomalies. Magnetic Resonance Imaging (MRI) reveals closed-lipped schizencephaly in the right frontal-parietal area, an absent septum pellucidum, and characteristics suggestive of Septo-Optic Dysplasia (SOD). Visual impairments and episodic symptomatic epilepsy further substantiate these findings.

From the MRI report: "Closed-lipped schizencephaly is evident, characterized by a gray matter-lined tract extending from the right frontoparietal region toward the ependymal surface of the posterior body of the right lateral ventricle. Although no direct communication with the lateral ventricle is observed, a slight protrusion from the ependymal surface points toward the schizencephaly region." To clarify, the patient's closed-lipped schizencephaly denotes abnormal brain development, evidenced by an irregular opening in the right frontoparietal area. A gray matter-lined tract stretches from this opening towards the posterior body of the right lateral ventricle. While there is no direct linkage between the tract and ventricle, a minor bulge on the ventricle's surface near the opening indicates developmental abnormalities. The patient is also missing a brain structure known as the septum pellucidum.

The absent septum pellucidum, a thin membrane that ordinarily divides the brain's hemispheres, is essential for regulating the flow of cerebrospinal fluid, which serves to cushion and protect the brain. Notably, the optic nerves and optic chiasm, key structures for vision, appear diminished in size.

Accompanying this complex neurological portrait is a multifaceted medical history, featuring diabetes, hypertension, asthma, and a range of anxiety disorders. The patient's premature birth at 7 weeks may have influenced the development of late-maturing cerebral regions like the TPJm, a particularly relevant detail in light of the subsequent schizophrenia diagnosis.

The patient exhibits a marked interest in theories of consciousness and a delayed understanding of Theory of Mind (ToM). Auditory processing inconsistencies, such as difficulties in discerning speech or song lyrics, point to functional irregularities in Wernicke's area—an area essential for language comprehension and proximal to the affected region.

### The Discussion & Comparison

Situated at the complex intersection of the parietal and temporal lobes, the Medial Temporoparietal Junction (TPJm) functions as a neural hub essential for various interconnected roles. Positioned above the ears towards the back of the skull, it serves as a crossroads for multiple neural pathways. For instance, while the parietal lobe specializes in spatial cognition and sensory processing, the temporal lobe is focused on auditory perception and memory. Together, these functions form the bedrock of social cognition, crucial for interpreting both our environment and the actions of others. This complex neural landscape is further elucidated by neuroimaging studies, which have revealed distinct brain regions activated during tasks related to theory of mind. Specifically, the temporo-parietal junction (both right and left) and the posterior cingulate cortex activate selectively during efforts to understand a protagonist's thoughts, whereas the medial prefrontal cortex shows a broader activation pattern across various social cognition tasks. Given the patient's unique neuroanatomical features, such as closed-lipped schizencephaly in the right frontal-parietal region, this area warrants particular attention for its potential impact on the social cognition deficits often associated with schizophrenia.

The TPJm metaphorically operates as the conductor of a neural symphony, orchestrating diverse elements to produce a cohesive social experience. It serves as a linchpin in the framework of Theory of Mind (ToM), the cognitive ability that enables us to perceive others as independent beings with their own thoughts, feelings, and intentions. Neuroimaging studies centered on tasks related to false belief have identified the medial prefrontal cortex (mPFC) and TPJ as integral structures in ToM. Due to its multifunctional role and the confluence of numerous cerebral regions, a dysfunction in the TPJm could instigate the range of social and sensory challenges commonly seen in schizophrenia—as exemplified by the patient's enduring difficulties in this area.

Additional complexity arises when considering the TPJm's developmental trajectory. This cerebral region is among the last to reach full maturation, making it particularly susceptible to dysfunctions such as synaptic "over-pruning," a leading hypothesis in schizophrenia research. This protracted development might attenuate the TPJm's sensitivity to key stimuli, like emotional cues or intentions, particularly when exacerbated by factors like premature birth. In this patient, born 7 weeks early and displaying late maturation of ToM, these developmental vulnerabilities dovetail strikingly with theories positing that late-maturing cerebral regions are more susceptible to conditions like schizophrenia.

Schizophrenia, with its enigmatic origins, is typically examined through an integrative lens encompassing genetics, environmental factors, and complex neurological mechanisms.  

The TPJm stands out as a central subject in this discourse due to its pivotal role in regulating social and sensory functions—areas frequently compromised in schizophrenia.

Recent research has revealed that abnormalities in midline brain structures, such as the absent septum pellucidum, occur more frequently among individuals diagnosed with schizophrenia and related mental conditions. One extensive study examined 639 patients with various psychotic or mood disorders alongside 223 control subjects. The findings indicate that midline brain abnormalities were substantially more prevalent among patient cohorts, underscoring a potential common etiological factor across multiple mental health conditions, including schizophrenia. In the case of our patient, the absence of the septum pellucidum not only aligns with these general findings but also adds weight to the hypothesis that such midline irregularities may play a key role in the neurodevelopmental origins of disorders like schizophrenia.

Septo-optic dysplasia (SOD) presents another compelling overlap in the exploration of brain malformations, psychiatric disorders, and our patient's case. Characterized by optic nerve hypoplasia and midline brain developmental anomalies, including the missing septum pellucidum, SOD manifests a spectrum of clinical symptoms ranging from visual impairments to hormonal imbalances, sleep disturbances, and developmental delays. Errors in perceiving facial expressions are believed to contribute to the variety of symptoms found in patients with schizophrenia. Our patient's specific features of septo-optic dysplasia align with these broader observations.

Given its multi-hormonal influence, the functions of the limbic system's pituitary gland extend well beyond its endocrine roles. Notably, the pituitary is often undersized or malformed in patients with SOD. Such abnormalities could have extensive implications for mental health, as the gland's hormonal secretions can affect neurotransmitter levels, stress responses, and other neurochemical balances, which are often disrupted in conditions like schizophrenia.

In our patient's situation, who has not only schizophrenia but also insulin-dependent type 2 diabetes, the pituitary gland assumes added importance. Considering the gland's secretion of hormones like ACTH, which influence cortisol levels, another interconnection emerges.

In examining the complex etiology of schizophrenia, recent investigations have identified noteworthy anomalies in gray matter volume (GMV) and cortical gyrification. One study singled out abnormal GMV in the right prefrontal area, a brain region closely associated with the evaluation of beliefs. This part of the brain also demonstrates structural quirks that seem to underpin the processing of fear, anxiety, and threat in patients with delusional disorders. These insights suggest that unique features of cortical structure, possibly arising from diverse evolutionary and genetic origins, could differentially contribute to the emergence and development of paranoid-type delusional disorders.

In another revealing study, heightened right prefrontal cortex (PFC) gyrification was observed among individuals at high risk for schizophrenia. This increase in cortical complexity appeared to mark an atypical trajectory of right prefrontal development among those who eventually received a schizophrenia diagnosis. The research additionally uncovered a distinct correlation between age and right PFC white matter volume, thereby adding another dimension to our understanding of the developmental factors that contribute to schizophrenia.

Situated in the lower posterior portion of the medial surface of the frontal lobe, the septal area consists of the lateral and medial septum, which are intricately linked with the septum pellucidum. The lateral septum (LS) serves diverse functions related to emotional, motivational, and spatial behavior. It further modulates interactions between the hippocampus and other vital brain regions like the ventral tegmental area, which plays a role in goal-directed behavior. Neuronal activity in the LS is modulated by factors such as speed, acceleration, and spatial location, as well as by reward context, thereby serving a potentially pivotal role in environmental assessment and motivational drives.

Interestingly, the lateral septum's functionality is regulated by inhibitory GABA and excitatory glutamate neurotransmitters. Research on juvenile rats has demonstrated that levels of both neurotransmitters rise during social play. While GABA levels seem consistent across sexes, glutamate has a more pronounced role in female social play. Inhibiting glutamate receptors in the LS led to a notable decrease in social play among females but not among males, indicating that neurotransmission in the LS may serve both universal and sex-specific roles in the regulation of social behaviors. Bleuler's 1950 characterization of schizophrenia underscored a "splitting of thoughts from feelings," and symptoms like emotional flatness and anhedonia have been considered core features since the disorder's initial descriptions. Patients with schizophrenia frequently misinterpret social cues and display impaired social skills. Symptoms like persecutory delusions often arise as misinterpretations of social interactions and events, connecting the LS to schizophrenia and our patient's case.

Another enigmatic structure in the septal area is the septum pellucidum. Although often mentioned in anatomical discussions, its functional role remains largely speculative. While commonly viewed as a mere anatomical barrier, its neural connections to the hippocampus and hypothalamus hint at a more intricate function as a relay station between these crucial brain regions. Likewise, the septal nuclei, despite being poorly understood, appear to participate in various functions.

The septal nuclei serve as critical elements of the limbic system, a cluster of subcortical structures often inaccurately reduced to mere emotional centers. These nuclei, in fact, participate in an expansive range of brain functions. They receive afferent neural connections from essential limbic components like the hippocampus, amygdala, and hypothalamus, as well as the dopamine-rich ventral tegmental area. Conversely, they extend efferent neural projections to many of these same regions, thus functioning as both receivers and transmitters of neural information.

One of the inaugural functions ascribed to the septal nuclei was in the domain of reward processing. Seminal experiments by James Olds and Peter Milner demonstrated that rats found electrical stimulation of the septal nuclei to be rewarding. These robust findings catalyzed the hypothesis that this region could be a pivotal part of the brain's reward circuitry. While subsequent research has redirected attention towards areas like the ventral tegmental area and nucleus accumbens, the septal nuclei continue to be of investigative interest. They contribute to the medial forebrain bundle, a neural conduit linking to the hypothalamus and ventral tegmental area, which is instrumental in activating dopamine neurons in response to rewarding stimuli. This dopaminergic system plays a critical role in the reward pathways that often become aberrant and disconnected from normative cognition in individuals with schizophrenia.

Furthermore, the septal nuclei are significantly implicated in learning and memory, largely due to their intricate connections with the hippocampus. These structures collectively constitute what is commonly termed the septo-hippocampal complex. The hippocampus primarily receives its neural inputs from the septal nuclei via a neural fiber bundle known as the fornix.

Although the septal nuclei play roles in diverse psychological and behavioral dimensions—from social behavior to the expression of fear—their specific functions remain nebulous. Abnormalities in septal activity are associated with a range of psychiatric conditions, including depression and schizophrenia.

Complementing their multifaceted functions in reward processing, learning, and memory, the septal nuclei add layers of complexity to our understanding of disorders like schizophrenia. Meanwhile, the septum pellucidum, frequently sidelined in neuroanatomical dialogues, is gaining recognition for its significance. Operating as a central nexus, it routes visceral information via the hypothalamic autonomic system to pivotal brain structures such as the hippocampus, amygdala, and habenula. Additionally, the septum pellucidum contributes to vital feedback mechanisms that modulate the body's internal state, encompassing variables like sleep and hunger. Its roles in regulating consciousness, sleep, and emotional reactions to environmental cues further underscore its multifaceted nature.

This structure functions as a key node in the neural circuits underlying diverse mental processes, including self-maintenance, food acquisition, sexual behavior, and autonomic homeostatic adaptations. In the absence of this feedback loop, there could be disruptions in autonomic regulation, manifesting as anomalies in temperature, thirst, and hunger responses, as well as distorted perceptions of physical needs—such as experiencing hunger when satiated, or feeling fatigued despite adequate rest.

The existing literature compellingly associates the absence of the septum pellucidum with a multitude of psychiatric conditions, including schizophrenia, affective psychosis, self-mutilation, developmental delays, atypical psychosis, and bipolar disorder. The organ's intricate role in modulating consciousness, sleep, emotional responses, and autonomic functions underlines its significance in maintaining mental and physiological stability. In schizophrenia patients, emotions are notably dysfunctional, characterized by a misinterpretation of social cues and a dissociation between cognition and emotion.

The situation gains additional complexity when considering the links between the absence of the septum pellucidum and other neurological conditions such as porencephaly, cerebellar hypoplasia, and internal malformations. De Morsier's syndrome is also implicated, extending the range of affected tissues beyond the brain to include both the pituitary gland and the cerebral cortex.

When an absence of the septum pellucidum is concurrent with schizophrenia, the consequences for an individual's neurological and psychological health are considerable. For example, one case involving a middle-aged adult with chronic schizophrenia who also lacked a septum pellucidum serves as a valuable reference point for understanding this neural structure's role in the origins of schizophrenia.

The absence of the septum pellucidum often coexists with Septo-Optic Dysplasia (SOD), a rare congenital disorder that impacts the development of midline brain structures. As a component of the limbic system, the septum pellucidum is implicated in various emotional and behavioral functions. The existing body of work indicates a robust correlation between septum pellucidum agenesis and several psychiatric conditions, including schizophrenia and bipolar disorder. Neural connections from this structure extend to the frontal lobes, emphasizing its potential role in a myriad of emotional and behavioral functions. Given these extensive interconnections, the septum pellucidum could very well be a critical variable in the neurological architecture of disorders like schizophrenia.

Closed-lipped schizencephaly is an uncommon cerebral malformation that occurs during fetal development, characterized by abnormal clefts typically lined with gray matter within the cerebral hemispheres. When these clefts manifest in the Right Frontal-Parietal (RFP) lobes, they can obstruct the 'top-down' neural signals directed towards the Temporoparietal Junction (TPJ). This interference can result in the flawed processing of social and sensory information, thus exacerbating the dysfunction commonly observed in conditions like schizophrenia. Given the potential of these clefts to disrupt normative neural signaling, they should be regarded as another critical variable in the complex neural milieu associated with schizophrenia.

Pioneering studies, such as the 2007 research by Paul and colleagues, underscore the potential relevance of structural abnormalities like schizencephaly in our understanding of schizophrenia. In an optimally functioning brain, negative coupling between higher-order cognitive regions—namely, the prefrontal cortex and the Temporoparietal Junction (TPJm)—ensures proper information processing for social cognition and other intricate operations. Yet, this regulatory mechanism frequently becomes dysfunctional in individuals with schizophrenia. Consequently, the aberrant signaling can interfere with the functionality of the TPJm, resulting in a broad spectrum of problems ranging from sensory processing deficits to emotional dysregulation. The presence of schizencephaly, especially in the Right Frontal-Parietal (RFP) lobes, may amplify these disruptions, thus further fueling the genesis of schizophrenia.

### Conclusion

The enigmatic nature of schizophrenia persists, despite the multitude of theories and research aimed at unraveling its complexities. However, through an interdisciplinary examination encompassing neurology, psychiatry, and even congenital brain abnormalities, we have begun to decipher the labyrinthine interplay of factors contributing to this psychiatric disorder. This intricate web involves key brain regions such as the pituitary gland, the temporo-parietal junction, the medial prefrontal cortex (mPFC), and the frontal and parietal lobes. The Medial Temporoparietal Junction (TPJm), in particular, emerges as a pivotal hub for social cognition and sensory processing. In shining a focused light on a singular, yet profoundly informative, patient case, this study ventures beyond merely identifying correlations. It aims to construct a more integrative understanding, edging us closer to recognizing potential causal mechanisms through which schizophrenia manifests.