David Baxter PhD
Late Founder
Hallucinations in Schizophrenia
Vladimir Maletic, MD, CME LLC
June 30, 2011
Question: “Why do people with schizophrenia experience hallucinations?"
Vladimir Maletic, MD: Hallucinations are one of the core “positive” symptoms of schizophrenia. They are often described as perceptual experiences without corresponding external or internal sensory stimuli.1 Although hallucinations in schizophrenia may involve different sensory modalities (auditory, visual, tactile, etc) our primary focus will be auditory verbal hallucinations (AVH). Approximately 60% to 80% of patients with schizophrenia2 at some point in their illness “hear voices,” making auditory hallucinations one of the most frequent and fundamentally disturbing symptoms. Patients often report hearing words, intrusive disparaging comments, fragments of conversations, multiple voices arguing, and sometimes commands urging them to act. Most often the voices are different than one’s own. One in four patients will experience AVHs that are not responsive to medication treatment.1
Let us begin our conversation by briefly reviewing the anatomy and physiology of auditory processing. In healthy individuals highly integrated neural loops process sensory information assigning it meaning and emotional value, and determining if it is of internal or external origin. For example, auditory signals are conducted from sensory organs (ears) via cochlear nerves, its corresponding nuclei and mesencephalic relay centers to thalamic receptive fields. From there, information is conveyed to the primary auditory cortex (AI) in the Heschl’s gyrus of the temporal lobe. Superior temporal lobe and adjacent temporal-parietal junction (including inferior parietal lobe) and inferior frontal gyrus also contain language centers and secondary association zones1 allowing spoken word to be incorporated into a wider social communication context. Arcuate fasciculus is a band of white matter forming principal connection between frontal and temporo-parietal language areas.3 Loops that include connections between auditory cortex and meso-temporal limbic areas (hippocampal-parahippocampal complex) provide for emotional associations and language-based memory. Additionally, cortico-striatal-thalamo-cortical circuitry plays a major role in speech generation, imagery, and perception.4 Cortico-thalamic-cerebellar circuits are involved in filtering neocortical input and interpretation of inputs.5
Despite intensive studies pathophysiology of AVH in schizophrenia is not fully elucidated. There are several confounding issues: a) schizophrenia is probably not a homogeneous diagnostic category; b) auditory hallucinations may have a different character: from simple words to multiple different voices arguing—we cannot assume that these phenomena have the same neurobiological underpinning; c) studies have used different methodologies, including diverse imaging techniques (PET, fMRI, etc) and different ways of communicating presence of hallucinations; d) patient samples differ in age, illness duration, medication status, gender, and ethnicity, and; e) sample sizes are often quite small.
Functional imaging studies utilized PET and fMRI to evaluate hallucination as a state or a trait. State studies compare brain activity during presence and absence of hallucinations in the same participants; by contrast trait studies make comparisons between participants with schizophrenia who have suffered from hallucination, ones who have never hallucinated, and healthy controls.2
Trait studies. A recent meta-analysis has found decreased activity in left superior and middle temporal lobes in hallucinating patients with schizophrenia compared to participants who had no history of hallucinations (these areas include primary and associative auditory cortices involved in speech perception). Additionally, hallucinating participants also exhibited hypoactivity in inferior frontal gyrus (IFG) an area that incorporates Broca’s convolution, involved both in preparation for overt speech and production of inner speech. Lesser activity in anterior cingulate cortex, an area involved in self-monitoring, may reflect a propensity of hallucinating patients to misinterpret their own inner speech as alien.2
State studies. Two recent meta-analyses identified increased activation in IFG and adjacent pre-central gyrus (both components of Broca’s area) in hallucinating patients. Furthermore patients with schizophrenia experiencing hallucinations also had greater activity in their inferior parietal lobule (IPL, a part of speech processing Wernicke’s area).1,2 One of the studies also noted elevated activity in right anterior insula, an area that has an analogue role to the left-sided Broca’s area . Both are involved in syntactic processing and verbal imagery, lending support to suggestions that impaired language lateralization may be conducive to emergence of AVH. Elevated activity in associative auditory areas in middle and superior temporal gyri also differentiated hallucinating patients from the ones who did not share their state.
Finally, abnormal activity in parahippocampal-hippocampal area was observed in hallucinating patients. Since these areas play a major role in verbal and contextual memory, it is possible that memory related processes may play a role in generating AVH. A rare PET imaging study evaluated brain metabolic changes in unmedicated first-episode schizophrenic patients. In addition to already described temporal lobe changes, this study also noted altered activity in dorsal medial prefrontal cortex (dmPFC) and cerebellum.5 dmPFC has been previously identified as an area involved in internal self representation. Its dysfunction combined with aberrant cerebellar processing in hallucinating patients may be reflected in misattribution of inner speech as an external event. In summary, it appears that hallucinations may be an outcome of aberrant activation within a distributed neural network involved in perception, generation, and monitoring of speech, and verbal memory related processes.1,2,5
Structural studies. Voxel-based analysis utilizing MRI found correlation between severity of auditory hallucinations and structural changes in several cortical areas.6 Affected areas included superior and middle temporal gyri (including primary and secondary auditory areas), ILP (encompassing Wernicke’s speech receptive area), and posterior cingulate cortex (involved in switching from default network resting activity to active attention). Other studies have described abnormal cortical gyrification in chronically hallucinating patients with schizophrenia, pointing to neurodevelopmental predilection to AVH.1 Findings of structural imaging studies are echoed by pathohistological evidence. Cytological studies of primary auditory and association cortices have discovered diminished volume of pyramidal neurons and reductions of dendritic spines and buttons in the brains of patients suffering from schizophrenia.7 Previous studies have also noted impaired prosody in schizophrenic patients: manifested as difficulty with speech intonation and recognition of the emotional tone of spoken content. Limited capacity to distinguish between questions and statements, sincerity, and sarcasm further impedes social functioning.7
Alterations in anatomical and functional connectivity. Arcuate fasciculus is the main connection between frontal and temporo-parietal language areas. Diffusion tensor imaging studies have detected a relationship between disrupted integrity of this white matter bundle and severity of hallucinations in patients with schizophrenia.3 These imaging findings most likely correspond with altered cytoarchitecture of axons and supportive glia cells. Furthermore, cytological studies have identified dysfunction and reduced numbers of oligodendroglia in patients with schizophrenia.7 Functional connectivity computed from fMRI data demonstrated robustly greater connectivity in the loop linking ILP-Wernicke’s area with IFG-Broca’s complex and putamen, distinguishing hallucinating from non-hallucinating patients and healthy controls.4 It is plausible to conclude that hyperconnectivity within corticostriatal circuitry may not only predispose patients to hallucinations but also reflect intensity of auditory hallucinatory experiences in individuals with schizophrenia.
Summary of data indicates that aberrant pattern of activity, in distributed language-processing and producing cortical and subcortical areas, may predispose patients with schizophrenia to auditory hallucinations. Convergent data implicate functional, structural, and connectivity alterations in synergistically disrupting language-based neural processing, resulting in confusion and misinterpretation.
References
Vladimir Maletic, MD, CME LLC
June 30, 2011
Question: “Why do people with schizophrenia experience hallucinations?"
Vladimir Maletic, MD: Hallucinations are one of the core “positive” symptoms of schizophrenia. They are often described as perceptual experiences without corresponding external or internal sensory stimuli.1 Although hallucinations in schizophrenia may involve different sensory modalities (auditory, visual, tactile, etc) our primary focus will be auditory verbal hallucinations (AVH). Approximately 60% to 80% of patients with schizophrenia2 at some point in their illness “hear voices,” making auditory hallucinations one of the most frequent and fundamentally disturbing symptoms. Patients often report hearing words, intrusive disparaging comments, fragments of conversations, multiple voices arguing, and sometimes commands urging them to act. Most often the voices are different than one’s own. One in four patients will experience AVHs that are not responsive to medication treatment.1
Let us begin our conversation by briefly reviewing the anatomy and physiology of auditory processing. In healthy individuals highly integrated neural loops process sensory information assigning it meaning and emotional value, and determining if it is of internal or external origin. For example, auditory signals are conducted from sensory organs (ears) via cochlear nerves, its corresponding nuclei and mesencephalic relay centers to thalamic receptive fields. From there, information is conveyed to the primary auditory cortex (AI) in the Heschl’s gyrus of the temporal lobe. Superior temporal lobe and adjacent temporal-parietal junction (including inferior parietal lobe) and inferior frontal gyrus also contain language centers and secondary association zones1 allowing spoken word to be incorporated into a wider social communication context. Arcuate fasciculus is a band of white matter forming principal connection between frontal and temporo-parietal language areas.3 Loops that include connections between auditory cortex and meso-temporal limbic areas (hippocampal-parahippocampal complex) provide for emotional associations and language-based memory. Additionally, cortico-striatal-thalamo-cortical circuitry plays a major role in speech generation, imagery, and perception.4 Cortico-thalamic-cerebellar circuits are involved in filtering neocortical input and interpretation of inputs.5
Despite intensive studies pathophysiology of AVH in schizophrenia is not fully elucidated. There are several confounding issues: a) schizophrenia is probably not a homogeneous diagnostic category; b) auditory hallucinations may have a different character: from simple words to multiple different voices arguing—we cannot assume that these phenomena have the same neurobiological underpinning; c) studies have used different methodologies, including diverse imaging techniques (PET, fMRI, etc) and different ways of communicating presence of hallucinations; d) patient samples differ in age, illness duration, medication status, gender, and ethnicity, and; e) sample sizes are often quite small.
Functional imaging studies utilized PET and fMRI to evaluate hallucination as a state or a trait. State studies compare brain activity during presence and absence of hallucinations in the same participants; by contrast trait studies make comparisons between participants with schizophrenia who have suffered from hallucination, ones who have never hallucinated, and healthy controls.2
Trait studies. A recent meta-analysis has found decreased activity in left superior and middle temporal lobes in hallucinating patients with schizophrenia compared to participants who had no history of hallucinations (these areas include primary and associative auditory cortices involved in speech perception). Additionally, hallucinating participants also exhibited hypoactivity in inferior frontal gyrus (IFG) an area that incorporates Broca’s convolution, involved both in preparation for overt speech and production of inner speech. Lesser activity in anterior cingulate cortex, an area involved in self-monitoring, may reflect a propensity of hallucinating patients to misinterpret their own inner speech as alien.2
State studies. Two recent meta-analyses identified increased activation in IFG and adjacent pre-central gyrus (both components of Broca’s area) in hallucinating patients. Furthermore patients with schizophrenia experiencing hallucinations also had greater activity in their inferior parietal lobule (IPL, a part of speech processing Wernicke’s area).1,2 One of the studies also noted elevated activity in right anterior insula, an area that has an analogue role to the left-sided Broca’s area . Both are involved in syntactic processing and verbal imagery, lending support to suggestions that impaired language lateralization may be conducive to emergence of AVH. Elevated activity in associative auditory areas in middle and superior temporal gyri also differentiated hallucinating patients from the ones who did not share their state.
Finally, abnormal activity in parahippocampal-hippocampal area was observed in hallucinating patients. Since these areas play a major role in verbal and contextual memory, it is possible that memory related processes may play a role in generating AVH. A rare PET imaging study evaluated brain metabolic changes in unmedicated first-episode schizophrenic patients. In addition to already described temporal lobe changes, this study also noted altered activity in dorsal medial prefrontal cortex (dmPFC) and cerebellum.5 dmPFC has been previously identified as an area involved in internal self representation. Its dysfunction combined with aberrant cerebellar processing in hallucinating patients may be reflected in misattribution of inner speech as an external event. In summary, it appears that hallucinations may be an outcome of aberrant activation within a distributed neural network involved in perception, generation, and monitoring of speech, and verbal memory related processes.1,2,5
Structural studies. Voxel-based analysis utilizing MRI found correlation between severity of auditory hallucinations and structural changes in several cortical areas.6 Affected areas included superior and middle temporal gyri (including primary and secondary auditory areas), ILP (encompassing Wernicke’s speech receptive area), and posterior cingulate cortex (involved in switching from default network resting activity to active attention). Other studies have described abnormal cortical gyrification in chronically hallucinating patients with schizophrenia, pointing to neurodevelopmental predilection to AVH.1 Findings of structural imaging studies are echoed by pathohistological evidence. Cytological studies of primary auditory and association cortices have discovered diminished volume of pyramidal neurons and reductions of dendritic spines and buttons in the brains of patients suffering from schizophrenia.7 Previous studies have also noted impaired prosody in schizophrenic patients: manifested as difficulty with speech intonation and recognition of the emotional tone of spoken content. Limited capacity to distinguish between questions and statements, sincerity, and sarcasm further impedes social functioning.7
Alterations in anatomical and functional connectivity. Arcuate fasciculus is the main connection between frontal and temporo-parietal language areas. Diffusion tensor imaging studies have detected a relationship between disrupted integrity of this white matter bundle and severity of hallucinations in patients with schizophrenia.3 These imaging findings most likely correspond with altered cytoarchitecture of axons and supportive glia cells. Furthermore, cytological studies have identified dysfunction and reduced numbers of oligodendroglia in patients with schizophrenia.7 Functional connectivity computed from fMRI data demonstrated robustly greater connectivity in the loop linking ILP-Wernicke’s area with IFG-Broca’s complex and putamen, distinguishing hallucinating from non-hallucinating patients and healthy controls.4 It is plausible to conclude that hyperconnectivity within corticostriatal circuitry may not only predispose patients to hallucinations but also reflect intensity of auditory hallucinatory experiences in individuals with schizophrenia.
Summary of data indicates that aberrant pattern of activity, in distributed language-processing and producing cortical and subcortical areas, may predispose patients with schizophrenia to auditory hallucinations. Convergent data implicate functional, structural, and connectivity alterations in synergistically disrupting language-based neural processing, resulting in confusion and misinterpretation.
References
- Jardri R, Pouchet A, Pins D, Thomas P. Cortical activations during auditory verbal hallucinations in schizophrenia: a coordinate-based meta-analysis. Am J Psychiatry. 2011;168(1):73-81.
- Kuhn S, Gallinat J. Quantitative meta-analysis on state and trait aspects of auditory verbal hallucinations in schizophrenia. Schizophr Bull. 2010;[Epub ahead of print].
- de Weijer AD, Mandl RC, Diederen KM, et al. Microstructural alterations of the arcuate fasciculus in schizophrenia patients with frequent auditory verbal hallucinations. Schizophr Res. 2011;[Epub ahead of print].
- Hoffman RE, Fernandez T, Pittman B, Hampson M. Elevated functional connectivity along a corticostriatal loop and the mechanism of auditory/verbal hallucinations in patients with schizophrenia. Biol Psychiatry. 2011;69(5):407-414.
- Horga G, Parellada E, Lomena F, et al. Differential brain glucose metabolic patterns in antipsychotic-na?ve first-episode schizophrenia with and without auditory verbal hallucinations. J Psychiatry Neurosci. 2011;36(1):100085.
- Nenadic I, Smesny S, Schlosser RG, Sauer H, Gaser C. Auditory hallucinations and brain structure in schizophrenia: voxel-based morphometric study. Br J Psychiatry. 2010;196(5):412-413.
- Lewis DA, Sweet RA. Schizophrenia from a neural circuitry perspective: advancing toward rational pharmacological therapies. J Clin Invest. 2009;119(4): 706-716.
