Final Report Summary - VOICE ("Hearing voices" - From cognition to brain systems)
The "VOICE" project set focus on a single symptom, auditory verbal hallucinations (AVHs), rather than the diagnostic category of schizophrenia. This was motivated from the perspective of narrowing the complexity of the phenotype and thereby increasing the possibility of a breakthrough in understanding the underlying mechanisms. The "VOICE" project set up a series of empirical studies, using a dichotic listening experimental paradigm, and with functional magnetic resonance imaging (fMRI) to uncover neuronal correlates. The experiments were designed from the predictions of a theoretical model that was advanced by Hugdahl et al. (2009) and which stated that AVHs are speech perceptual experiences that are mis-attributed to an external agent, which draws available attention capacity towards the "voices", and which are outside of cognitive control, as if the "voices" control the patient, not the other way around. The first experiments followed a simple logic; if AVHs are experienced as someone speaking to the patient, it would follow that a possible neuronal origin would be in the speech perception areas in the brain. Speech perception is localized to the upper portion of the posterior region of the temporal lobe, primarily on the left side. Thus, a first ypothesis was that AVHs are caused by spontaneous activity on this brain region, in the absence of an external auditory stimulus, and that this interferes with processing of external stimuli. Dichotic listening is a behavioral experimental technique that probes the functional integrity of the speech perception areas, which is indexed through better recall of dichotically presented syllable sounds from the right ear, called a right-ear advantage (REA). Hugdahl et al. (2012) showed that the magnitude of the REA was negatively correlated with frequency and severity of AVs, which was evidence that AVHs interfered with the processing of externally presented speech sounds. This was empirical support for the ature of AVHs, and the interference prediction from the "VOICE model (Hugdahl et al., 2009). In a meta-analysis of fMRI studies of AVHs done in our laboratory, Kompus et al. (2011) showed that patients who experienced AVHs had spontaneous neuronal activation in the same brain region as was probed by dichotic listening, thus, linking the reduced REA to increased spontaneous neuronal activity. A new dichotic listening experiment, now also probing for attention and cognitive control capacity, next showed that AVHs interfered with both capacity for attention focus and ability for cognitive control, both factors showing negative correlations with frequency and severity of AVHs (Hugdahl et al., 2013). This finding was followed-up with a therapy trial, using an iPhone app, for training of cognitive control capacity in a small sample of selected patients. Any fMRI result must have a corresponding change in transmitter function at the synaptic level. We used MR spectroscopy to show that concentrations of the transmitter metabolites glutamate and glutamine were elevated in the temporal and frontal lobe areas in hallucinating patients, which may indicate different neurochemistry in hallucinating and non-hallucinating patients (Hugdahl et al., 2015). A final study (Kompus et al., 2013) investigated differences and similarities in behavioral and fMRI measures between clinical and non-clinical individuals experiencing AVHs. The results showed differences both with regard to behavioral and fMRI measures, which is evidence that both perceptual and cognitive factors play different roles in clinical and non-clinical individuals, despite the fact that both groups experience "hearing voices".
The major achievements can be summarized as follows:
1. The proposal questioned previous inner speech and traumatic memory explanations for auditory hallucinations, instead advancing a perceptual model. The results from the VOICE project have clearly favored a perceptual model, and that auditory hallucinations are initiated through abnormal speech perception processes. This has been shown in both behavioral (e.g. Hugdahl et al., 2012), and brain imaging (e.g. Kompus et al., 2011; Karabay et al., 2013) data. The meta-analysis by Kompus et al. (2011) is a key milestone output from the project in this respect since it clearly showed that areas in the peri-Sylvian region in the brain are spontaneously activated in the absence of an external sound source, and that these regions are the same regions that have previously been shown to be activated in healthy individuals in the presence of an external sound source (e.g. van den Noort et al., 2008). Thus, our findings provided empirical support to the model outlined in the VOICE proposal. Another meta-analysis from France, published at about the same time (Jardri et al., 2011) and with similar results, strengthened the interpretations of the Kompus et al. (2011) findings.
2. A second major achievement is the "VOICE" model (summarized in Hugdahl, 2015) for the explanation of both the initiation and the maintenance of auditory hallucinations as the interaction between a hyper-activated temporal lobe bottom-up system and hypo-activated frontal lobe top-down system, such that the spontaneous initiation of auditory hallucinations, from the temporal lobe, are not inhibited, or suppressed, because of a dysfunctional top-down, or cognitive, system. The finding by Hugdahl et al. (2015) of increased glutamate concentrations in temporal lobe areas in hallucinating patients is also direct evidence that the hyper-activation in temporal lobe areas may be caused by excessive excitatory transmitter function, since glutamate is the major excitatory neurotransmitter in the brain. The suggestion in Hugdahl (2015) that GABA dysfunction may be causing frontal lobe hypo-activation (see also Brix et al., 2015) may be the corresponding transmitter explanation for the top-down hypo-activation, considering that GABA is the major inhibitory transmitter in the brain. If these findings and suggestions would withstand replications and critical analysis it would be a potential new avenue to the development of new medications that would be tailored to a single symptom, auditory hallucinations, rather than the diagnostic category as such, schizophrenia.
3. A third major achievement from the project was the introduction of "levels of explanation" (Hugdahl, 2015), as a theoretical template for analysis of data related to auditory hallucinations. With "levels of explanations" is meant that any mental phenomenon can be studied and explained at different levels of study, from the cultural and social level to the molecular and genetic level, and that scientific progress must involve as many levels as possible in a vertical direction, not just expanding horizontally on a single level (which is the more common approach). With this in mind, the study by Hugdahl et al. (2015) where we managed to show a significant positive correlation between frequency and severity of auditory hallucinations on the one hand, and concentration of the neurotransmitter glutamate in a region in the temporal lobe (also frontal) provided a first demonstration of the neurochemistry of auditory hallucinations, and that it was possible to move beyond functional imaging data at the brain systems level of explanation. The study by Hugdahl et al. (2015) is to my knowledge the first empirical study of a direct relationship between degree of hallucinationary experiences and change in a related neurotransmitter, with possible implications for development of new treatments.
4. A fourth major achievement was the introduction of smartphone app-technology as a vehicle for cognitive training for the patients to cognitively learn to withstand and ignore the "voices" once they were initiated. This was thus an attempt to develop new cognitive training and therapy vehicles to activate the top-down system, through cognitive training. The training was in the grant proposal suggested to be done on a PC in the laboratory or clinic, where the patient would come every day, or on a pre-set schedule, and was based on the dichotic listening experimental paradigm that was originally developed in my laboratory many years ago (Hugdahl & Andersson, 1986). By coincidence, a young PhD student who was in my lab when the training was about to start, suggested that we instead develop an iPhone app for this purpose. This first seemed non-serious to me, but I changed my mind when I realized that with an app it would be possible to apply the training procedure in all kids of social situations, not possible with a PC-based training schedule, when sitting on the bus, in a café, among other people etc. etc., and that the procedure would have no stigmatizing side-effects since the patients would look like any other individual on the bus, with their ear-plugs plugged in and fiddling with their smart-phones. The training produced mixed results in the sample that was tested, statistically the results were not significant when comparing pre- versus post-training measures, while at the same time the patients qualitatively reported that the training had helped them to "resist the voices" and that they now had a procedure they could use in any social situation when the "voices made themselves heard" and just having a tool to focus on helped them. Having once developed an iPhone app for cognitive training, we then more or less by accident found another application for app-technology in hallucinations, or schizophrenia research. This was the real-time symptom sampling approach that smart-phone technology allows (see Hugdahl, 2015), and which we suggested could be used as an app to sample the experience of an hallucinatory episode along three core dimensions (emotional content, cognitive control, spatial localization) in real-time. With such an approach the disadvantages with interview-based approaches can be overcome and literally new data can be obtained which will allow for analysis of variables related to the experience of auditory hallucinations with short life-cycles, not possible from traditional interview scales.
References:
Brix et al. 2015, Frontiers Human Neuroscience, http://www.ncbi.nlm.nih.gov/pubmed/26157380
Hugdahl et al. 2009, Frontiers in Neuroscience, http://www.ncbi.nlm.nih.gov/pubmed/19753095
Hugdahl et al., 2012, Schizophrenia Research, http://www.ncbi.nlm.nih.gov/pubmed/22796149
Hugdahl et al., 2013, Schizophrenia Research, http://www.ncbi.nlm.nih.gov/pubmed/23664588
Hugdahl et al., 2015, Schizophrenias Research, http://www.ncbi.nlm.nih.gov/pubmed/25542859
Hugdahl (2015), World J of Psychiatry, http://www.wjgnet.com/2220-3206/full/v5/i2/193.htm
Hugdahl, K. Andersson, L. 1986, Cortex, 22, 4l7-432
Jardri et al. American Journal Psychiatry, http://www.ncbi.nlm.nih.gov/pubmed/20952459
Karabay et al. 2013, http://www.ncbi.nlm.nih.gov/pubmed/
Kompus et al., 2011, Neuropsychologia, http://www.ncbi.nlm.nih.gov/pubmed/21872614
Kompus et al., 2013, Frontiers in Psychology, http://www.ncbi.nlm.nih.gov/pubmed/23630479
van den Noort et al., 2008, Neuroimage, http://www.ncbi.nlm.nih.gov/pubmed/
The major achievements can be summarized as follows:
1. The proposal questioned previous inner speech and traumatic memory explanations for auditory hallucinations, instead advancing a perceptual model. The results from the VOICE project have clearly favored a perceptual model, and that auditory hallucinations are initiated through abnormal speech perception processes. This has been shown in both behavioral (e.g. Hugdahl et al., 2012), and brain imaging (e.g. Kompus et al., 2011; Karabay et al., 2013) data. The meta-analysis by Kompus et al. (2011) is a key milestone output from the project in this respect since it clearly showed that areas in the peri-Sylvian region in the brain are spontaneously activated in the absence of an external sound source, and that these regions are the same regions that have previously been shown to be activated in healthy individuals in the presence of an external sound source (e.g. van den Noort et al., 2008). Thus, our findings provided empirical support to the model outlined in the VOICE proposal. Another meta-analysis from France, published at about the same time (Jardri et al., 2011) and with similar results, strengthened the interpretations of the Kompus et al. (2011) findings.
2. A second major achievement is the "VOICE" model (summarized in Hugdahl, 2015) for the explanation of both the initiation and the maintenance of auditory hallucinations as the interaction between a hyper-activated temporal lobe bottom-up system and hypo-activated frontal lobe top-down system, such that the spontaneous initiation of auditory hallucinations, from the temporal lobe, are not inhibited, or suppressed, because of a dysfunctional top-down, or cognitive, system. The finding by Hugdahl et al. (2015) of increased glutamate concentrations in temporal lobe areas in hallucinating patients is also direct evidence that the hyper-activation in temporal lobe areas may be caused by excessive excitatory transmitter function, since glutamate is the major excitatory neurotransmitter in the brain. The suggestion in Hugdahl (2015) that GABA dysfunction may be causing frontal lobe hypo-activation (see also Brix et al., 2015) may be the corresponding transmitter explanation for the top-down hypo-activation, considering that GABA is the major inhibitory transmitter in the brain. If these findings and suggestions would withstand replications and critical analysis it would be a potential new avenue to the development of new medications that would be tailored to a single symptom, auditory hallucinations, rather than the diagnostic category as such, schizophrenia.
3. A third major achievement from the project was the introduction of "levels of explanation" (Hugdahl, 2015), as a theoretical template for analysis of data related to auditory hallucinations. With "levels of explanations" is meant that any mental phenomenon can be studied and explained at different levels of study, from the cultural and social level to the molecular and genetic level, and that scientific progress must involve as many levels as possible in a vertical direction, not just expanding horizontally on a single level (which is the more common approach). With this in mind, the study by Hugdahl et al. (2015) where we managed to show a significant positive correlation between frequency and severity of auditory hallucinations on the one hand, and concentration of the neurotransmitter glutamate in a region in the temporal lobe (also frontal) provided a first demonstration of the neurochemistry of auditory hallucinations, and that it was possible to move beyond functional imaging data at the brain systems level of explanation. The study by Hugdahl et al. (2015) is to my knowledge the first empirical study of a direct relationship between degree of hallucinationary experiences and change in a related neurotransmitter, with possible implications for development of new treatments.
4. A fourth major achievement was the introduction of smartphone app-technology as a vehicle for cognitive training for the patients to cognitively learn to withstand and ignore the "voices" once they were initiated. This was thus an attempt to develop new cognitive training and therapy vehicles to activate the top-down system, through cognitive training. The training was in the grant proposal suggested to be done on a PC in the laboratory or clinic, where the patient would come every day, or on a pre-set schedule, and was based on the dichotic listening experimental paradigm that was originally developed in my laboratory many years ago (Hugdahl & Andersson, 1986). By coincidence, a young PhD student who was in my lab when the training was about to start, suggested that we instead develop an iPhone app for this purpose. This first seemed non-serious to me, but I changed my mind when I realized that with an app it would be possible to apply the training procedure in all kids of social situations, not possible with a PC-based training schedule, when sitting on the bus, in a café, among other people etc. etc., and that the procedure would have no stigmatizing side-effects since the patients would look like any other individual on the bus, with their ear-plugs plugged in and fiddling with their smart-phones. The training produced mixed results in the sample that was tested, statistically the results were not significant when comparing pre- versus post-training measures, while at the same time the patients qualitatively reported that the training had helped them to "resist the voices" and that they now had a procedure they could use in any social situation when the "voices made themselves heard" and just having a tool to focus on helped them. Having once developed an iPhone app for cognitive training, we then more or less by accident found another application for app-technology in hallucinations, or schizophrenia research. This was the real-time symptom sampling approach that smart-phone technology allows (see Hugdahl, 2015), and which we suggested could be used as an app to sample the experience of an hallucinatory episode along three core dimensions (emotional content, cognitive control, spatial localization) in real-time. With such an approach the disadvantages with interview-based approaches can be overcome and literally new data can be obtained which will allow for analysis of variables related to the experience of auditory hallucinations with short life-cycles, not possible from traditional interview scales.
References:
Brix et al. 2015, Frontiers Human Neuroscience, http://www.ncbi.nlm.nih.gov/pubmed/26157380
Hugdahl et al. 2009, Frontiers in Neuroscience, http://www.ncbi.nlm.nih.gov/pubmed/19753095
Hugdahl et al., 2012, Schizophrenia Research, http://www.ncbi.nlm.nih.gov/pubmed/22796149
Hugdahl et al., 2013, Schizophrenia Research, http://www.ncbi.nlm.nih.gov/pubmed/23664588
Hugdahl et al., 2015, Schizophrenias Research, http://www.ncbi.nlm.nih.gov/pubmed/25542859
Hugdahl (2015), World J of Psychiatry, http://www.wjgnet.com/2220-3206/full/v5/i2/193.htm
Hugdahl, K. Andersson, L. 1986, Cortex, 22, 4l7-432
Jardri et al. American Journal Psychiatry, http://www.ncbi.nlm.nih.gov/pubmed/20952459
Karabay et al. 2013, http://www.ncbi.nlm.nih.gov/pubmed/
Kompus et al., 2011, Neuropsychologia, http://www.ncbi.nlm.nih.gov/pubmed/21872614
Kompus et al., 2013, Frontiers in Psychology, http://www.ncbi.nlm.nih.gov/pubmed/23630479
van den Noort et al., 2008, Neuroimage, http://www.ncbi.nlm.nih.gov/pubmed/