Neural Substrates of Hallucinations

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Hallucinations are the perception of sensory information that is not present in reality. They can occur in any of the senses or even co-occur simultaneously. This phenomenon is most associated with a diagnosis of paranoid schizophrenia. The current view on the neural basis of hallucinations is that of a modality-specific model, meaning that abnormal connectivity in certain sensory brain regions result in corresponding sensory hallucinations[1]. For example, it has been shown that auditory hallucinations result from abnormal connectivity between Heschl’s gyrus and other brain regions[2]. For the most part research has focused on auditory hallucinations due to their high prevalence[1]. However, other sensory hallucinations are now being examined. By looking at the abnormalities in sensory networks, we can garner insight into how these systems work in normal cases. This research is also important due to the fact that hallucinations greatly decrease a person’s quality of life; for example, difficulty interacting in social situations. By understanding the neural basis of hallucinations, improved treatments can be developed to help those affected.

Auditory Hallucinations

Audio representation of an auditory hallucination,

Auditory hallucinations (AHs) are the most common form of hallucination. They are experienced by approximately seventy percent of schizophrenia patients[3]. These usually involve the perception of voices from either external or internal space, known as auditory verbal hallucinations (AVHs), but can also be nonverbal. These pervasive voices heard by schizophrenia patients commonly have the same functions: addressing the subject to do a certain action or inhibiting a certain action[4]. However, eighty-four percent of people who experience AVHs report that the voices are giving them commands; this leads to the common report by schizophrenia patients that “they made me do it” [4],[5]. Research has mostly focused on the role of the temporal lobe, and specific regions within the temporal lobe, as the main contributor to AHs.

Structural Changes in the Temporal Lobe

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Figure 1: The cerebral cortex,

The temporal lobe is the auditory centre of the brain. The thalamus directs all incoming auditory stimuli to the temporal lobe for further processing[6]. With this in mind, it is no wonder why so much of AH research has looked at the temporal lobe as the cause of this phenomenon.

Though most research has focused on the relationship between functional abnormalities in the temporal lobe and AHs, there are studies that have tried to determine a structural difference in the temporal lobe. One such study found that there was a pattern of structural abnormalities in the left superior temporal, left temporoparietal and right prefrontal regions in those experiencing AHs. Their results demonstrated a correlation between severity of hallucinations and a decrease in volume in the left transverse temporal gyrus of Heschl, left (inferior) supramarginal gyrus, and the middle/inferior right prefrontal gyri[7]. With these findings, it was concluded that there was a hallucination-specific pattern of brain changes in the frontotemporal network, where sounds and language are processed[7].

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Figure 2: Reduction of grey matter density in schizophrenia patients with
auditory hallucinations (Hugdahl et al., 2008)

Other brain morphometry studies demonstrated structural changes in the right temporoparietal junction, a crucial part of the dorsal (“where”) auditory pathway, including reduced white matter volume and sulcus displacements when compared to healthy controls[8]. Differences in grey matter volume have also been examined. van Swam and colleagues investigated grey matter volume (cortical thickness) in patients with chronic AVHs. Their findings showed a reduction in cortical thickness in regions associated with speech processing and increased grey matter volume in self-monitoring regions[9]. They went on to interpret these findings by suggesting that additional demand is put on the self-monitoring region, due to the ambiguous information it receives from the speech processing areas, which results in the changes in cortical plasticity[9]. Significant reduction in grey matter has also been found in the peri-Sylvian region in the left temporal lobe, a region involved in speech perception[10]. However, research into the association between grey matter and auditory hallucinations has produced many contradictory findings. This makes it difficult to determine the role of such structural changes in AHs.

Heschl's Gyrus Activation during Auditory Hallucinations

Heschl's gyrus, also known as the transverse temporal gyrus, lies within the primary auditory cortex in the temporal lobe. When auditory information enters the brain, Heschl’s gyrus is one of the first regions to process this information. Therefore, Heschl’s gyrus has long been associated with auditory hallucinations. Dierks et al.originally demonstrated the increased activation of this region, using fMRI, when paranoid schizophrenia patients were experiencing AHs[11]. This was the first direct evidence of the involvement of the primary auditory cortex in AHs. This laid the groundwork for the current view of modality-specific hallucinations. Recent studies have shown that abnormal projections between left Heschl’s gyrus and other brain regions could increase a person’s vulnerability to AHs (see Figure 3)[12]. When compared to healthy controls, there was decreased functional connectivity between Heschl’s gyrus and the right hippocampal formation and mediodorsal thalamus but increased connectivity with left frontoparietal regions in patients suffering from AHs[12].

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Figure 3: Brain regions temporally activated through connection with Heschl's gyrus.
Top: Patients with AHs, Middle: Patients without AHs, Bottom: Healthy Controls
(Shinn et al., 2013)

Furthermore, there are documented structural differences in the Heschl’s gyri of those who experience AHs versus healthy controls. Such changes include increased fiber-tracks connecting Heschl’s gyrus with other auditory regions, increased volume of the right Heschl’s gyrus, and overall greater volume of Heschl’s gyri in AVH patients versus controls[13]. These findings also support the idea that with the increase in activation there is an increase in neural plasticity which leads to an increase in volume[13]. Yet, studies have illustrated the negative correlation between grey matter reduction and the frequency of AHs. Neckelmann et al. proposed that the reduction of grey matter in Heschl’s gyrus may lead to spontaneous neural firing which in turn causes hallucinations[14]. Similarly, the correlation between grey matter volume and symptom expression has been thought to be dimensional rather than categorical, meaning that frequency of AHs increases with the increased structural changes[15].

Dysfunciton of the Speech Perception Networks

Since the majority of AHs involve a verbal component, the speech perception networks have continually been implicated as contributors to AVHs. As previously mentioned, many of the structural brain changes associated with AHs are within the speech perception networks. In this section, more specific speech generation regions will be examined. Wernicke’s and Broca’s areas are particularly important due to their roles in speech perception and production respectively[16]. Dysfunction in the speech generation network results in secondary activation of Wernicke’s and Broca’s area resulting in hallucinations, activation of vocal musculature, and subvocal speech (SVS)[16]. However, direct stimulation or damage of Wernicke's area does not result in AVHs; this leads to the assumption that vocal musculature and subvocal speech are associated with AVHs as well[16].

Auditory verbal hallucinations are most often thought to be caused by the misattribution of inner speech as an external voice[17]. Many studies have implicated dysfunction in the processing of inner speech in patients with schizophrenia. There is evidence that in the schizophrenic brain there is a weakened response of brain regions involved with verbal self-monitoring, including the right temporal, parietal, parahippocampal and cerebellar cortex, when an increased demand is put on the processing of inner speech; this leads to the projection of inner speech into the external environment[17]. Jones and Fernyhough also reported a decrease in activation in the middle and superior temporal gyri in association with those who experience AVHs[4].

Visual Hallucinations

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Figure 4: Example of a visual hallucination,

After auditory hallucinations, visual hallucinations (VHs) are the second most common form of hallucination experienced by schizophrenia patients; affecting up to 32 percent[3]. These can include seeing faces, bodies, scenes that are not really there or perceiving their surroundings incorrectly[3]. This type of hallucination is thought to be the result of deficits in reality-monitoring which leads to confusion between visual mental images and perception. For example, Brébion et al. showed such patients 32 items as either a picture or a written word. Later when asked to recall which form an object was presented in, the VH group made more misattribution errors; there was an increased tendency to remember words as pictures in those with VHs[18]. It has also been proposed that the presence of visual hallucinations could be a result of cholinergic dysfunction in the frontal cortex and the ventral visual pathway[19]. This is a common deficit between schizophrenia and other diseases associated with visual hallucinations[19]. Unlike auditory hallucinations, visual hallucinations have also demonstrated lateralization. VHs are more likely to present in the visual field processed by the dominant cerebral hemisphere in chronic schizophrenia pateints[20].

The Hippocampal Formation and Occipital Lobe

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Figure 5: Activation map of the left and right hemisphere during a visual hallucination; demonstrating
the visual areas activated during each type of hallucinations, i.e. face, body, or scene (Oretel et al., 2007)

The occipital lobe is responsible for the processing of all visual stimuli that enters the brain while the hippocampal formation’s main function is associated with memory[3].Oertel et al. demonstrated that these two brain regions work together to produce VHs. Using fMRI, increased brain activity was produced in higher visual regions and the hippocampal formation when one was experiencing a VH. Interestingly, the visual area activated during the hallucination corresponded to the content of the hallucination. For example, the fusiform face area would be active when the subject was experiencing a hallucination featuring a face (See Fig. 5)[3]. The activation of the hippocampal formation was attributed to the retrieval of visual memories which contribute to the vividness of the hallucinations[3]. These findings have also been seen by Amad et al.; they discovered specific connectivity patterns between the hippocampus and the occipital lobe which corresponded to visual hallucinations alone[21].

Olfactory Hallucinations

Our understanding of olfactory hallucinations (OHs), in spite of being fairly prevalent, is still very limited. This type of hallucination involves the misperception of an odor. They occur in approximately 13-17% of schizophrenia patients[22]. The few studies that have been conducted have yet to shed much light on the neural basis of OHs. However, Arguedas et al. recently found preliminary evidence that olfactory hallucinations like auditory and visual hallucinations are modality-specific[23]. When asked to determine whether an odor was real or imagined, patients who experienced OHs performed significantly worse than those that experienced only AVHs. Conversely, the AVH group had more difficulty than the OH group when the same task was administered but with a sound instead of an odour[23]. Another recent study has implicated the orbitofrontal cortex (OFC) as a neural substrate of OHs. When schizophrenia patients with OHs were compared with patients with AVHs, the OH group demonstrated impairments associated with OFC dysfunction[24]. Further research is needed to understand the structural and functional brain regions responsible for olfactory hallucinations.

Tactile Hallucinations

Tactile hallucinations, the perception of bodily sensations without external stimuli, are only reported by four percent of schizophrenia patients[3]. With such a low prevalence rate, little research has been done in regards to the neural substrates of tactile hallucinations. However, it has been shown that there is a correlation between the frequency of olfactory hallucinations and the severity of tactile hallucinations[25]. Much like olfactory hallucinations, a great deal of research is necessary to further our knowledge of how tactile hallucinations occur.

An example of someone experiencing a multi-modal hallucination. "Seven" is
seen as a person shaped like the number seven but will also give commands.

Multi-modal Hallucinations

Multi-modal hallucinations are a very rare and intriguing type of hallucination. Though many schizophrenia patients can experience hallucinations in more than one modality, few will experience hallucinations in two sensory modalities simultaneously. Of the reported occurrences of multi-modal hallucinations, it is most commonly a combination of auditory and visual hallucinations[26].

Case Study of Visual/Auditory Verbal Hallucinations

Due to the rarity of multi-modal hallucinations, no experimental studies have been conducted but case studies have been compiled to attempt to further our grasp of their neural basis. Hoffman and Varanko examined three cases where patients had visual/auditory verbal hallucinations. These patients described seeing mouth and lip movements accompanied by auditory verbal hallucinations[26]. They theorized that due to fact that those who experience AVHs have difficulties with speech perception; these patients relied heavily on lip-reading. This in turn would increase the chance of cross-modal, top-down processing of visual information during speech perception[26]. Further research would have to be done to support this hypothesis.

Role of the Frontal Lobes in Hallucinations

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Figure 6: Activation of middle frontal gyrus during AVHs, seen in blue (Looijestijn et al., 2013)

Considering the frontal lobes are the centre for executive control in the brain, research is beginning to look more deeply into the possible role they have in the creation of hallucinations in schizophrenia. As with other studies within the other modalities, it has been shown that there is decreased functional connectivity between the frontal lobes and other brain regions. In particular, reduction in functional connectivity between the frontal and temporal lobe, specifically in speech perception and speech production areas, has been shown to occur in schizophrenia patients when talking[27]. This decrease in communication is thought to contribute to the misattribution of inner speech to external voices[27]. More specifically, the dorsolateral prefrontal cortex (DLPFC) has been associated with external AVHs. The DLPFC is a crucial region for visospatial working memory and auditory localization processing; because of this it is proposed that the DLPFC is the output region for the auditory “where” pathway[28]. This means that upstream modalities project to the DLPFC which in turn connects to other prefrontal regions depending on what function is needed. The overall effect is that inner speech is projected into external space resulting in an AVH[28]. This has important implications for the theory of schizophrenia being a network disease. As other studies have shown, the findings by Looijestijn et al. illustrate that fact that many symptoms and deficits present in schizophrenia can be associated with faulty neural networks within the brain.

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