Judith Ford Presentation - SRF Webinar Sep 13, 2012

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Judith Ford Presentation - SRF Webinar Sep 13, 2012

  1. 1. Neurophysiological Studies of Auditory Verbal Hallucinations Thomas Dierks CAVEAT Fisher Derek event related potentials) has a Electrophysiology (EEG and EEG-based long history in studies of schizophrenia Ford Judy and serious mental illness. Christoph Herrmann Most were focused on establishing mental illness as a brain-based Daniela Hubl disease rather than a choice (c.f., Szasz, The Myth of Mental Illness). They largely succeeded. Jochen Kindler However, few were specifically focused on understanding the Thomas Koenig pathophysiology of specific symptoms. Daniel Mathalon I will be talking about those. Kevin Spencer Werner Strik Ford JM, Dierks T, Fisher DJ, Herrmannvan Lutterveld et al. Remko CS, Hubl D, Kindler J, Schizophr Neurophysiological Studies of Auditory Verbal Hallucinations. Bull. 2012.Report from the International Consortium for Hallucination Research and Related Symptoms Institute of Psychiatry, London, UK September 13, 2011
  2. 2. I). Approachs to study auditory hallucinations• A. Assessments of State – Symptom Capture • Periods of hallucinations and non-hallucinations are compared within a patient • These studies take two forms: passive studies and probe studies.• B. Assessments of Trait – Hallucinators vs. Non-hallucinators • Hallucination severity is sometimes used in “individual differences” studies.• C. Mechanistic Studies of Trait – Spontaneous neural activity model – Inter-regional communication in the brain – Self-monitoring failures
  3. 3. A. Assessments of State Resting State Symptom Capture Studies with Time-Frequency Analyses As reviewed by Van Lutterveld et al 1, before the era of anti-psychotic medications, depth electrocorticography studies were sometimes conducted in conjunction with neurosurgery for relief of severe psychotic symptoms. Other than providing an historical note, old EEG findings are not easy to incorporate into the contemporary literature with more sophisticated data collection and analysis. Angelopoulos EEG 14 Increase in phase coupling in the alpha band, both inter- and intra-hemispherically between temporal and frontal lobes.Highlights of traditional EEG/MEG analysis in symptom capture studies:Little consistency regarding the frequency of the neural activity.Good consistency regarding involvement of right and left auditory cortex, consistent with sMRIand fMRI From Van Lutterveld et al, 2011.
  4. 4. A. Assessments of State*Shortening of this microstate might indicate a Resting State Symptom Capture Studiespremature termination of the delicate balance Using ERPs/ERFs to External Probesbetween goal-directed and salience-drivenprocesses, compatible with the observedpsychopathology. *•ERPs elicited by probes during an hallucination are smaller and later, suggesting•the involvement of the auditory cortex in the generation of the hallucination.•The line is busy. From Van Lutterveld et al, 2011.
  5. 5. A. Assessments of State Advantages and Disadvantages• 1. Advantages• Ability to observe neural activity preceding and during a hallucinatory experience. – Provides temporal and some spatial information. – Nevertheless, few studies have used EEG in symptom capture.• 2. Disadvantages• The unknown contributions from shifting attention and motor responses when the patient signals the beginning and ending of a hallucination. – Symptom capture studies require patience from the research team and cooperation and insight from the patient.
  6. 6. B. Assessments of Trait using Auditory Event-Related Potentials (ERPs)• Comparing patients who do hallucinate to patients who do not. – It is typically not known, if the patients who do hallucinate happen to be hallucinating during data acquisition.• Many of the studies that compare hallucinators to non-hallucinators use event-related brain potentials (ERPs) to auditory probes – because they can reveal where and when in the brain processing of auditory information is compromised by the tendency to experience auditory verbal hallucinations.
  7. 7. Auditory Event-Relatedcomponents Where do the different Potential—ERP come from and what do they reflect? (a.k.a., evoked potential [EP], auditory evoked potential [AEP]) Middle latency responses: P3a and P3b: Generator: Primary auditory cortex. Generators: Frontal and parietal lobes, respectively. Function: They reflect early auditory Function: They reflect the allocation of processing. attention, either elicited passively (orienting) or effortfully. MMN: Generators: Secondary auditory cortex and frontal lobes. Function: It reflects automatic registration of auditory sensory memory. N1: Brain stem responses: Generators: Primary andGenerators: 8th nerve secondary auditory cortex, butthrough brain stem is affected by frontal lobes.Function: They reflect the Function: N1 reflects hearing Fromintegrity of the early levels and auditory SpringerImages.com, (Adapted from Picton et al. 1974; Risslingauditory system. perception. et al, 2010.)
  8. 8. What would it Event-Related Potential—ERP Auditory mean if a particular component were smaller (a.k.a., evoked potential [EP], auditory evoked potential [AEP]) in patients who were hallucinating? Middle latency responses: P3a and P3b: Generator: Primary auditory cortex. Generators:Voices are preventinglobes, respectively. Frontal and parietal Voices are disrupting processing of Function: They reflect the allocation of Function: They reflect early auditory orienting or attending to external auditory events in primary attention, either elicited passively or effortfully. processing. external auditory auditory cortex. events, respectively. MMN: Generators: Secondary auditory Voices are disrupting the cortex and frontal lobes. registration of auditory Function: It reflects automatic sensory memory. registration of auditory sensory memory. N1: Brain stem responses: Generators: Primary andGenerators: 8th nerveVoices are disrupting secondary auditory cortex, but Voices are disrupting processingthrough brain externalprocessing of stem is affected by frontal events in of external auditory lobes.Function:events reflect theauditory They in the brain Function: N1 reflects hearing primary and secondary auditory Fromintegrity of the earlystem and perhaps thalamus. levels and auditory Hubl et cortex (as shown by SpringerImages.com, (Adapted from Picton et al. 1974; Risslingauditory system. perception. al., 2007). et al, 2010.)
  9. 9. Are these components are affected by the Auditory Event-Related Potential—ERP hallucinatory trait? (a.k.a., evoked potential [EP], auditory evoked potential [AEP]) Middle latency responses: P3a and P3b: Generator: Primary auditory cortex. Generators: that over 100 paperslobes,reported Considering Frontal and parietal have respectively. Derek Fisher’s lab has reported Function: They reflect P1 and Function: They reflect the allocation of attention, P300 reductions in schizophrenia, it is surprising that relationships between early auditory processing. severity across subjects. either elicited passivelyrelationship between P300 only 3 have reported a or effortfully. hallucination and AVH. Recall the Caveat: Failures to find relationships between ERPs and the trait to hallucinate could be due to a failure to find a positive MMN: relationship or UmbrichtGenerators: Secondary auditory and Kjrles (2005) reported that failure to test for such a of the 22 cortex and frontal lobes. MMN studies done in relationship. schizophrenia, onlyIt reflectsrelationships Function: 3 found automatic between registration of auditory sensory MMN and AVH. memory. Since then, Derek Fisher’s lab has N1: reported small MMNs are related to AVH Brain stem responses: Generators: Primary and severity. thGenerators: 8reports ofThere are no nerve secondaryno reports of N1 but There are auditory cortex, Either the storage of auditory informationthrough brain stem beingbrain stem responses is affected by frontal lobes. being affected by the trait of in short term (echoic) memory or theFunction: They reflect theaffected by hallucination Function: N1 reflects hearing hallucinations. registration that a deviant occurred, or Fromintegritytrait. earlystate or of the levels and auditory SpringerImages.com, (Adapted both, is altered in patients whoal. 1974; Rissling from Picton et have aauditory system. perception. pre-disposition to hallucinate et al, 2010.)
  10. 10. B. Assessments of Trait using ERPs to Probes Advantages and Disadvantages• 1. Advantages• Comparing patients who do and do not hallucinate on MEG and EEG-based methods is far simpler than comparing periods with hallucinations to periods with no hallucinations.• The few successful studies using this method are consistent with the findings of the symptom capture literature: – Auditory cortex is “busy” in people who tend to hallucinate, interfering with processing auditory information as early as 50ms (P1)after stimulus onset and as late as 200ms (MMN) and 300 ms (P300).• Study by van Lutterveld and colleagues (2010) avoided a lot of these problems 2. Disadvantages• Trait studies typically compare one group of patients who hallucinate to another group of patients by usingnot. who do healthy people who hallucinate. Surprisingly, theyof an ERP component may be affected by larger P300s thanbut it will benon- by a – The amplitude found that these people had the trait to hallucinate, healthy affected lot of other individual differences that overwhelm the differences due to the tendency to hallucinate. hallucinating subjects suggestingstudy the same persontypically seen symptomatic and once when – To address this question, we need to P300 reduction twice, once when in schizophrenia is not not. to the tendency to hallucinate. due• The preponderance of schizophrenia patients are medicated, and medication may decouple any potential relationship between symptoms and neurobiology by attenuating symptoms, while not affecting the ERP sensitivity to the propensity to experience those symptoms.• We may be more successful at finding relationships with enduring features of the disease (the diagnosis itself, or its subtypes) than with current symptoms.• Other symptoms may combine with hallucinations to affect the neurobiology but not the severity of the hallucinations.• Some drugs of abuse might affect the neurobiology but not the current severity of the symptoms.• Correlations between hallucinations and biology can only be as good as the assessment of hallucinations.
  11. 11. C. Summary of Mechanistic Models and Neurophysiological Findings• Most symptom capture and trait studies using EEG and ERPs point to involvement of left and right auditory cortex in AVH. • PET and fMRI reveal more areas are involved than just auditory cortex!• Remaining questions can be addressed with Mechanistic Models + fMRI data : Why is auditory cortex busier in hallucinators and during hallucinations?  Random noise increases sensitivity to weak signals through stochastic resonance (Jaramillo & Wiesenfeld, 1998), and patients with schizophrenia have “noisier” systems as indexed with EEG methods. Why do thoughts become conscious and audible?  Synchronized activity between key areas may promote conscious perception of unbidden thoughts (EEG; Angelopoulos et al, 2011; Melloni et al., 2007)  Hyper-connectivity between auditory cortex and putamen makes unbidden thoughts audible (fMRI data; Hoffman et al, 2011) Why do AVH have negative content?  Hyper-connectivity between amygdala and parahippocampal gyrus may promote the sense of uncertainty and suspiciousness (fMRI; Bhatt et al, 2012), and between putamen and auditory cortex may promote audible thoughts (fMRI; Ford et al, in prep). Why are percepts misperceived as coming from external sources?  Self-monitoring deficits (EEG data; Ford et al., 2007)
  12. 12. Ideas for future research• A. Combine EEG and fMRI methods• Unexplored is the how specific baseline states affect the processing of internal and external information that might serve as triggers for AVHs, or as a trigger to interrupt such experiences.• Such questions would require the combination of methods during symptom capture to assess relationship between baseline state (spectral EEG, fMRI measures of resting state connectivity) and ERPs to auditory probes (c.f., Hubl et al 2007).• B. More studies of mechanisms• Self-monitoring mechanistic studies offer translation to bench neuroscience and translation to other species, and hence open the door to invasive manipulations that are not possible with in vivo human studies. – For one example, studies like the ones reviewed above can be applied to animals who make social calls, such as song-birds (Brainard and Doupe, 2000) and non-human primates (Eliades and Wang, 2003). – In such an experiment, perturbations of the neurotransmitters implicated in schizophrenia might produce a pattern in the neural signature of the mechanism that resembles the pattern seen in schizophrenia patients who hallucinate.
  13. 13. Questions?For a copy of the paper:Judith.ford@ucsf.edu

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