Naturally occurring hallucinations in the waking state (i.e. not induced by drug effects, sleep or meditation) arise from a variety of physiological and psychological conditions. These include Schizophrenia, Parkinson's disease, Narcolepsy and epileptic seizures. Hallucinations also may occur in peripheral nervous system disorders, such as Guillain-Barré syndrome . The neurological bases for these hallucinations are diverse, however in many cases share commonalities. These may include activation of the primary sensory cortices , involvement of neurotransmitter systems such as cholinergic dysfunction , and abnormal cortical connections . Sleep disorders and dreaming have also been associated with hallucinations in many of these pathologies, including abnormal REM sleep  and hypocretin-1 deficiency . Research continues to examine the neurological bases of hallucinations in a variety of pathologies, which will provide insight not only into the causes and potential interventions for these abnormal experiences, but also the general processes of perception in the human brain.
|Sacks talks hallucinations|
|Discussion of hallucinations by acclaimed author and neuroscientist Oliver Sacks,
particularly in patients with Charles Bonnet syndrome.
Table of Contents
|Four Patients with Schizophrenia|
|Examples of what patients with Schizophrenia might experience.|
Schizophrenia is a current hot topic in a wide variety of fields in neuroscience and neuropsychology. In regards to hallucinations, schizophrenic patients have been a target of research in order to investigate the causes of symptoms of psychosis. For example, the July 2012 issue of Schizophrenia Bullet specifically addressed hallucinations in schizophrenic patients. The publications were compiled by members of the International Consortium on Hallucination Research, which holds meetings to discuss and share research, and the first of which was held only in 2011 (visit the site for more about this issue and conference). The growing body of research on hallucinations present in these patients is providing insight into both the nature of hallucinations in general, as well as the etiology of Schizophrenia and the potential interventions possible for specific symptoms. Visit Neural Substrates of Hallucinations for more detailed information on the neural structures and abnormalities associated with various types of hallucinations present in Schizophrenia.
Auditory Verbal Hallucinations
The most commonly experienced hallucinations by schizophrenic patients are auditory verbal hallucinations (AVH). For this reason, they have also received the most attention in research. The auditory sounds heard tend to be specifically verbal, implicating language centres. Indeed, one of the first SPECT studies on AVH demonstrated increased blood flow to Broca’s area. Studies have consistently demonstrated activation of the temporal cortices during auditory hallucinations, specifically bilateral language areas. An early study also suggested superior temporal lobe activation, as well as structural abnormalities in MRI .
(below) Figure A: Temporal lobe activation during auditory hallucination. Figure B: Not present in periods with no hallucinations .
Newer neurological studies utilizing EEG and MEG for AVH were reviewed by Ford et al., which tend to show activation of the frontal and temporal cortices during these experiences . In support of this, one recent meta-analysis of PET scans of patients experiencing AVH showed activation in fronto-temporal areas involved in speech generation and perception, and medial temporal lobe involved in verbal memory . fMRI studies have shown increased activity in the insular, anterior cingulate, and bilateral temporal cortices . Increased activity has also been demonstrated by fMRI studies in Heschl’s gyrus, implicating the primary auditory centre in these hallucinations .
Earlier studies have also implicated the hippocampus in auditory verbal hallucinations, as well as the parahippocampal region and subcortical structures, including nuclei of the thalamus, striatum and cerebellum , which has been supported by other studies . The role of limbic and subcortical structures aren't well understood; it may be that they add emotional content to the hallucinations, or provide memory retrieval of actual perceptual experiences. Recent studies have examined the areas activated preceding hallucinations to attempt to determine what triggers hallucinations in these patients. A recent MEG study showed that, consistent with past literature, AVH had left temporal cortex language area activation during the hallucinations, but were preceded by activation in memory areas (eg. hippocampus) . Changes in left parrahippocampal gyrus activation have also been observed before auditory hallucinations .
Given the frontal lobe activity demonstrated during AVH in these patients, the working memory deficits commonly seen in Schizophrenia, and the role of the parietotemporal speech areas in AVH, it has been proposed that auditory hallucinations may arise from abnormal connectivity between frontal and parieto-temporal areas involved in speech. This may result in problems identifying internal speech due the disconnection between planning and perception areas of speech ,  or abnormal activation of these centres . Connections between frontal and temporal areas have been shown to be abnormal in these patients , . Diffusion tensor imaging (DTI) studies have also demonstrated that abnormal tracts between frontal, temporal and parietal speech areas may result in random activation of these areas, and problems processing internal speech . In relation to this abnormal connectivity, structural analyses of Heschl’s gyrus have shown an increased volume in these patients , supporting the notion that structural abnormalities in, or abnormal connections between key regions of the brain may give rise to hallucinations.
While present in only a minority of patients with Schizophrenia and less studied, olfactory hallucinations have been shown to be predictive of more severe cases , and the implication of orbitofrontal cortex involvement also provides evidence for other associated problems in certain patients, for example involving affect. One recent study demonstrated patients who experience olfactory hallucinations performed worse on orbitofrontal tasks than healthy controls and patients with auditory verbal hallucinations . This subset of patients with a rare manifestation of frontal lobe abnormalities can aid in our understanding of the wide range of behavioural and executive deficits present in some patients with Schizophrenia. However, the role of the orbitofrontal cortex in these hallucinations is still unclear. Although olfactory perceptions can be induced by stimulation of the olfactory bulb, but not areas of the orbitofrontal cortex . Problems with olfaction have been reported in Schizophrenic patients, however they have not been shown to be linked with any neurological deficits . Olfactory hallucinations have in general been shown to be predictive of psychosis and more severe and worse cases in patients already diagnosed with psychosis . However, they are much more common in epilepsy and have been shown to be ameliorated with medication for epilepsy . Nonetheless, the severity of psychosis associated with olfaction merits continued study of olfactory hallucinations, hopefully aiding the identification of more at-risk patients, as well as more targeted treatments.
For a more in-depth background on Guillain-Barre Syndrome, visit the National Institute of Neurological Disorders and Stroke website.
Guillain-Barre Syndrome (GBS) is a disorder that results from damage to the peripheral nervous system, known as peripheral neuropathy . The onset is normally around four weeks, and it is associated with several subtypes of neuropathies that are diagnostically distinguished (for a review of the features of some of the subtypes, see Hughes & Cornblath, 2005 ). Symptoms include elevated cerebral spinal fluid proteins and psychological abnormalities ; specifically, sleep disorders and hallucinations have been characterized in some of these patients, that may shed light on the nature of hallucinations and their potential relationship with sleep (for more information on sleep and abnormalities associated with different facets, visit Sleep: The Great Enigma
Sleep and Hallucinations
A subset of patients with GBS experience hallucinations. These are most commonly hypnagogic (see Hallucinations During Sleep Paralysis for more information), and are associated with and more severe mental abnormalities . In terms of greater severity, patients who experience these symptoms tend to have greater nerve damage and higher cerebral spinal fluid protein (CSF) levels . It is often seen in conjunction with delusions and psychosis, in the most severe cases .
In a comprehensive and unique study, Cochen et al. (2005) examined a clinical group of severely affected GBS patients and found commonalities in those experiencing hallucinations, particularly autonomic dysfunction and abnormal aspects of REM sleep, which were present in all of these patients. The sleep abnormalities and REM disorder are consistent with other psychopathologies in which hallucinations are present. These abnormalities include shorter REM sleep, REM eye movements during other stages of the sleep cycle, changes in the structure of sleep in general, and movement present during REM sleep. Furthermore, as is also found in some patients with Narcolepsy, CSF hypocretin-1 levels also tended to be lower in these patients . These trends led the authors to characterize these hallucinations as “wakeful dreams”, and identified the primary cause as being a sleep disorder. Read this study online for a greater description of the methodology and results.
In support of this dream-like characterization, patients themselves have described their perceptual experiences as similar to those experienced during hypnagogic states, and being almost like a dream . It is possible that the cause of the disease is also responsible for the hallucinations. The peripheral dysfunction that occurs may block sensory and motor systems responsible for processing external stimuli; as in sleep, when these systems are naturally off, an inability to distinguish internally generated sensations from environmental ones may arise . This would help to explain the dream-like nature of the hallucinations, and is similar to what may occur in Schizophrenia with internally generated speech. Along these lines, given that the patients with the most severe neuronal loss, and therefore the greatest inability to communicate and move, are the ones that tend to experience hallucinations and elements of psychosis , it could be that the brain continues to produce neuronal activity which cannot be distinguished from external stimuli.
Although little research has been done on this disease, primarily due to its rare occurrence and frequent severity, it is likely that the cortical activation seen in patients with hallucinations would occur in the corresponding sensory areas, as seen in hallucinations in most other psychopathologies. This is consistent with the hypothesis that the perceptions arise from underactive sensory and motor systems.
Patients with Parkinson’s Disease may experience hallucinations that arise internally in addition to being real but wrongly perceived . Their visual hallucinations tend to be complex, usually of full objects or animals . Some may also experience tactile hallucinations, although more rarely. The presence of hallucinations and these abnormal perceptual experiences is often considered to be caused by pharmacological treatments (ie. dopamine); however, this is not the case for all patients and there are likely other additional explanations .
There are several proposed underlying causes of hallucinations in Parkinson’s Disease patients, including an imbalance of dopamine and cholinergic systems in the CNS, problems with the visual pathway from the eyes to the brain or in the extrastriate pathways, brainstem dysfunction, and sleep cycle abnormalities. These symptoms tend to occur in combination with each other , however they also all contribute to the occurrence of hallucinations on their own . Furthermore, more frequent hallucinations are associated with more advanced forms and severe cognitive impairment . Cognitive impairment, sleep dysregulation, brainstem dysfunction and visual abnormalities have been the most extensively studied and widely confirmed causes of visual hallucinations in Parkinson’s Disease patients.
Brain Substrates and Cognitive Impairments
Parkinson’s patients, particularly those who experience hallucinations and delusions, commonly have deficits in visual and frontal region functions. They demonstrate more severe cognitive impairment, particularly in executive control, as well as problems with the processing of visual information. Furthermore, higher amounts of Lewy bodies tend to be found in these brain areas, implicating them in the occurrence of hallucinations in these patients .
(right) Example of Lewy Bodies in brain cells. Taken from: http://www.nlm.nih.gov/medlineplus/lewybodydisease.html.
The presence of Lewy bodies in cortical areas have been confirmed to predict symptoms of dementia associated with Parkinson’s, including hallucinations . Neuroimaging studies report higher Lewy body counts in the frontal, temporal and parietal regions (among others) in patients with hallucinations . In particular, more severe cases associated with Lewy bodies in the parahhippocampal gyrus and inferior temporal lobe, which have also been implicated in hallucination symptoms in other psychopathologies (eg. Schizophrenia). An increasing number of Lewy bodies over time in areas such as the temporal lobes seem to be associated with the presence of hallucinations .
In accordance with more Lewy bodies in several distinct cortical regions, the decline of cognitive function has been strongly implicated in an increasing risk of hallucinations. The deterioration of cognitive abilities also leads to more severe symptoms, as patients without awareness of the fact that their hallucinations are not real tend to have the more severe cognitive dysfuntion, compared to patients with hallucinations who maintain awareness of reality . The fact that up to 70% of patients may develop hallucinations  as the disease progresses further suggests that more severe cases are predictive of these symptoms, and cognitive decline is a factor.
Longitudinally, these patients show greater problems with executive control and memory . The increasingly severe problems with executive function, and the presence of Lewy bodies in the frontal lobe which are predictive of cognitive impairments, strongly points to the frontal regions as playing a crucial role in the progression of the disease and development of associated symptoms, such as hallucinations. The fronto-striatal pathway has also been implicated in the presence of visual hallucinations; this further points to involvement of dopamine as well as the notion that impairment of frontal lobe functioning is a predictor of these symptoms .
The progression of the disease and the increasing prevalence of hallucinatory symptoms correlate with a distinct set of developing deficits, including accompanying decrease in activity of corresponding cortical areas and the presence of Lewy bodies in some of these. The activity of the brain during the actual visual hallucinations may be in the corresponding sensory areas; for example, in patients with Lewy bodies, activity has been shown in the primary visual cortex . This is consistent with studies of numerous psychopathologies implicating particular sensory areas as responsible for the perceptual experiences during hallucinations.
Sleep Abnormalities and Neurotransmitters
Sleep disorders have been estimated in 74-98% of patients  and are one of the primary causes of hallucinations cited. The hallucinations are also strongly associated with the presence of vivid dreams or REM disorders which, conversely, are also strongly associated with sleep irregularities. These associations imply an important connection between dreams, sleep dysregulation and the presence of hallucinations . Some of these sleep abnormalities include reduced total sleep time, long sleepless periods at night, and movement during REM sleep (consistent with Guillain-Barre Syndrome) . Patients also report sleepiness throughout the day that seems to be related to the disease as opposed to medications .
Due to the large amounts of activity during REM stages, these patients are likely not to be fully asleep, but are however having vivid dreams that are difficult to distinguish from reality. This is interesting in light of the fact that activation of extrastriate visual areas has been shown to be active during REM sleep  as well as during hallucinations in Parkinson’s and other psychopathologies (suggesting potential neural correlates between some hallucinations and dreams). This is also related to the types of hallucinations present in patients with narcolepsy, in particular the hypnagogic hallucinations that occur as they are waking up during a dream. It is possible that due to the excessive sleepiness during the day, the patients may experience sudden onset of REM sleep and therefore have daytime dreams that they have difficulties distinguishing from reality . The presence of frontal lobe deficits may further explain their problems with dissociating these experiences from reality, and the fact that they are often not phased by their symptoms . Consistent with this, REM sleep disorders have been shown to predict not only hallucinations but also more severe long term cognitive problems .
The presence of sleep abnormalities may have to do with neurotransmitter systems. This makes sense given that Parkinson’s is a dopaminergic disorder, and also the fact that neurotransmitters are intimately involved in the regulation of sleep and wake cycles, as well as the physiological activity associated with sleeping states. Serotonin is one implicated neurotransmitter. Patients with visual hallucinations have been demonstrated to have increased binding of the serotonin 2A receptor in several regions that have also been implicated as being involved in the presence of hallucinations. These include the prefrontal and orbitofrontal cortex, and areas of the ventral extrastriate pathway like the inferior temporal lobes, largely implicated in hallucinations in several psychopathologies including Parkinson’s . Consistently, it has been demonstrated that blocking the 5-HT3 receptor helps to reduce psychotic symptoms in these patients .
Cholinergic dysfunction may also be involved. A new technique known as Short-latency Afferent Inhibition (SAI; for more information, read recent Brain Stimulation article on SAI) has allowed researchers to examine the activity of cholinergic pathways, implicating them in patients with visual hallucinations. The presence of these abnormalities also predicts cognitive impairment .
(left) Simple schematic of cholinergic projections. Taken from: www.frontiersin.org.
As already mentioned, studies have confirmed that REM sleep disorder is predictive of cognitive deficits . Furthermore, brainstem dysfunction present in patients with REM sleep disorder and those in Parkinson’s with cognitive impairments have shown similar abnormalities, particularly in neurotransmitter system nuclei . Given the converging evidence that REM sleep disorder and cholinergic dysfuntion are predictive of cognitive impairment, as well as the potential involvement of cholinergic systems in Parkinson’s patients with cognitive impairment, a very recent article attempted to connect these findings and demonstrated that cholinergic dysfunction is predictive of cognitive deficits developing in these patients and, most importantly, that REM sleep disorder plays a role in their development .
While these connections remain to be fully understood, it does appear that neurotransmitter and brainstem dysfunction may play a role in the development of cognitive deficits and hallucinations present in Parkinson’s disease, and that REM sleep disorders are involved due to the same underlying sources. New research in this field is particularly important because these four have been the primary causes implicated in the development of hallucinations and more severe forms of Parkinson’s.
Tactile hallucinations are much rarer than visual hallucinations in these patients. One study reported eight patients with tactile hallucinations, offering case reports and potential underlying mechanisms. Evidence from these patients points to several possible problems; in at least some patients, the hallucinations could in fact be linked to dopamine levels from their treatments. They may also be associated with problems related to sleep, particularly REM disorder . Overall, the hypotheses concerning the underlying causes of tactile hallucinations, as well as the most at-risk patients, are generally the same as the more common hallucinations in this disease.
Narcolepsy is a sleep disorder characterized by excessive sleepiness during the day, and often occurs in conjunction with cataplexy (see Narcolepsy and REM Sleep for more information). It has commonly been associated with features of REM sleep, including sleep paralysis  (see Hallucinations During Sleep Paralysis for more details). Hallucinations are also commonly experienced by patients with Narcolepsy, particularly hypnagogic hallucinations which occur during transitional phases between sleeping and waking. Although the precise cause of these hallucinations remains unclear, they are most often discussed in relation to sleep and REM disturbances.
Hallucinations and Sleep
As in other psychopathologies, REM sleep has also been implicated in the presence of hallucinations and elements of psychosis in narcolepsy. REM sleep is important because elements of it may occur during sleep or waking states, helping to explain the occurrence of hallucinations at various times. Although these periods of REM-like experiences during waking states also occur in Parkinson’s and Schizophrenia, hallucinations in narcolepsy are most often related to sleep, have different features and constitute a different type of experience altogether . For example, hallucinations in these patients tend to be multimodal and reported as quite realistic, as opposed to other disorders in which the perceptual experiences are more separated from reality and it is clearer to the patient that they are hallucinating. This makes them more difficult to distinguish from dreams and reality; consistently, fewer patients with narcoleptic hallucinations report awareness of the fact that they are hallucinating than, for example, Parkinson’s patients .
Studies have demonstrated that these hallucinations are related to sleep paralysis , a unique association with narcolepsy and a feature of REM sleep disorders. In fact, REM sleep disorders have been directly implicated in the presence of hallucinations in narcoleptic patients . These hallucinations have been referred to as dreams, but in the waking state, primarily because of the physiological similarities between narcoleptic episodes and dreaming stages of sleep, as well as the multiple sensory perceptions that create a more “dream-like” hallucinatory experience .
As is the case for some incidents of Parkinson’s Disease, the hypocretin system has been reported to be associated with REM sleep disorder in narcoleptic patients . Specifically, it seems that patients with narcolepsy with cataplexy lack these cells in the lateral hypothalamus, resulting in improper motor regulation both during REM sleep (causing the symptoms of REM sleep disorder) as well as in waking states, resulting in cataplexy . In contrast, patients with Parkinson’s and narcolepsy without cataplexy may only have a partial hypocretin-1 deficiency, resulting in a difference in their symptoms and hallucinatory experiences . These initial findings remain to be investigated, but provide some basis for a potential cause of hallucinations in Narcolepsy, for which there is still no explanation.
Focal seizures occur in a localized area and sometimes present with hallucinatory experiences due to stimulation caused by cortical activity, either within the respective primary sensory cortex or eventually reaching the primary sensory cortex. There are a variety of causes and forms of epilepsy; the presence of hallucinations tends to be associated with partial epilepsy and includes auditory hallucinations and visual hallucinations. Unlike those in most psychopathologies, these hallucinations are linked to better understood phenomena and generally have identifiable sources. Seizures are also mentioned as features in Traumatic Brain Injury, Tone Deafness, Sexual Serial Killers and Parasites That Alter Host Behavior.
In epileptic patients, increased cerebral blood flow has been found in the primary auditory cortex during auditory hallucinations (consistent with other psychopathologies involving hallucinations due to activity of the sensory cortex associated with the perception)  and EEG measures showed that the seizures occurred in the temporal lobe. In general, the hallucinations may be caused by temporal lobe seizures occurring directly in Heschl’s gyrus, or originating elsewhere and causing stimulation of the primary auditory cortex . As demonstrated in Schizophrenia, auditory verbal hallucinations in particular may arise from improper fronto-temporal connections which cause an inability to distinguish internal from external speech.
(right) EEG during seizure, with auditory hallucinations . Characteristic pattern of activity in the temporal lobe.
One type of epilepsy in which auditory hallucinations occur frequently is genetic in origin and is known as autosomal dominant partial epilepsy with auditory features (ADPEAF) . EEG and SPECT have implicated the temporal region as the source of activation causing these hallucinations. It has also been referred to as autosomal dominant left temporal lobe epilepsy (ADLTE), a term first used by Pozza et al., 1999 . It has been suggested that the two seem to be the same  but the exact genetic make-up and symptoms still require research. Nevertheless, temporal lobe seizures and activation of auditory cortical areas appear to be a common cause of auditory hallucinations in epileptic patients.
It is well recognized that visual hallucinations in epileptic patients involve the occipital lobe. One particular cause of occipital lobe seizures is cortical dysplasia, in which abnormal development of the cortex in the occipital lobe causes malformed neurons to fire, resulting in epilepsy . In one case study, hallucinations were documented after the resection of a portion of the occipital lobe, in order to attempt to treat epilepsy due to cortical dysplasia .
Research has focused more on complex visual hallucinations occurring in patients resulting from damage to the eyes or occipital lobe. This includes Charles Bonnet Syndrome, which has been used to characterize visual hallucinations that occur in the elderly, normally after damage to the eyes. It is possible that regions of the brain become over activated as a way of compensating . As in other experiences of visual hallucinations, activation of the occipital lobes is primarily implicated. For more information on Charles Bonnet Syndrome, see review article in Survey of Opthalmology, as well as description mentioned by Oliver Sacks in video link.