Feasibility Electrical Stimulation Study for Visual Hallucinations

Improving Visual Hallucinations by Targeting the Visual Cortex With Electrical Stimulation: A Feasibility Study

The visual system has increasingly been recognized as an important site of injury in patients with schizophrenia and other psychoses. Visual system alterations manifest as visual perceptual aberrations, deficits in visual processing, and visual hallucinations. These visual symptoms are associated with worse symptoms, poorer outcome and resistance to treatment. A recent study using brain lesion mapping of visual hallucinations and identified a causal location in the part of the brain that processes visual information (visual cortex). The association between visual cortex activation and visual hallucinations suggests that this region could be targeted using noninvasive brain stimulation. Two case studies have found that brain stimulation to the visual cortex improved visual hallucinations in treatment resistant patients with psychosis. While promising it is unclear whether these symptom reductions resulted from activity changes in the visual cortex or not. Here we aim to answer the question whether noninvasive brain stimulation when optimally targeted to the visual cortex can improve brain activity, visual processing and visual hallucinations. The knowledge gained from this study will contribute to the field of vision by providing a marker for clinical response and by personalizing treatment for patients with psychosis suffering from visual symptoms. This grant will allow us to set the foundation for a larger more targeted study utilizing noninvasive brain stimulation to improve visual symptoms in patients with psychosis.

The visual system has increasingly been recognized as an important site of pathology in patients with schizophrenia and other psychoses. Visual system impairments manifest as visual perceptual aberrations, deficits in visual processing tasks, and visual hallucinations (VH). In psychosis spectrum disorders, increased visual aberrations are strongly correlated with worse hallucinations and delusions. It is also recognized that poorer performance on visual spatial working memory, visual integration, and velocity discrimination tasks are associated with greater negative symptoms (a major contributor to disability). VH are common in psychotic disorders (30-70% prevalence) and can be refractory to existing treatments. VH have been understudied in psychosis with much of the literature focusing on auditory hallucinations. Despite the neuroscientific and clinical significance of VH, the brain regions responsible are less clear. Functional neuroimaging studies have identified neural correlates of VH across multiple brain regions (lingual, fusiform, cuneus, lateral geniculate nucleus, and occipital cortex) and support hypotheses that increased visual cortex activity and sensory cortex over-stimulation generate VH. However, whether these neuroimaging findings represented a cause, consequence or incidental correlate of VH was unclear until recently. Using a newly validated technique termed lesion network mapping, researchers demonstrated that focal brain lesions having a causal role in the development of VH can occur in different brain locations, both inside and outside sensory pathways, and that these lesions are functionally connected to the lateral geniculate nucleus, a major relay center for the visual pathway. They also found that 98% of the subcortical and cortical lesions were connected to the exact same location in the extrastriate visual cortex. Therefore, the association between extrastriate visual cortex activation and VH would suggest this region may be optimal for modulation via brain stimulation. One method by which cortical excitability can be altered is through the use of transcranial electrical stimulation (tES), a non-invasive brain stimulation technique. High definition tES (HD-tES) is a refined version of tES with improved spatial precision of cortical stimulation. This involves the application of a weak electrical current (1-2 mA) delivered to the brain via scalp electrodes. The effects of tES modulate cortical excitability where anodal stimulation tends to increase (i.e. the resting potential becomes less negative) and cathodal stimulation tends to decrease the underlying membrane potential (i.e. the resting potential becomes more negative) (14,15). Studies have shown that tES can modulate visual cortical function in a polarity-dependent manner, where anodal stimulation can increase and cathodal stimulation can decrease the amplitude of the N70 component from the visual-evoked potential. While tES is a promising adjunctive treatment of auditory hallucinations and negative symptoms in schizophrenia, less is known about its role in treating VH. To date, two cases have been described where cathodal tES (i.e., outward current flow) over the occipital area was applied to patients experiencing treatment refractory VH, and this resulted in symptomatic improvement. Taken together, the recent lesion network mapping identifying the extrastriate visual cortex as a major source of VH in schizophrenia combined with these two single-patient case studies suggest that it may be possible to alleviate VH by designing a tES protocol that targets the extrastriate visual cortex bilaterally. Technological advances in noninvasive neuromodulation and electrical field modeling further allow us to create a tES protocol specifically guided by the results of lesion network mapping studies (i.e., using the exact Montreal Neurological Institute coordinates) with high spatial resolution (i.e., using HD-tES).

Two, twenty minute sessions of cathodal tDCS to the bilateral extrastriate visual cortex for 5 days (10 total sessions).

Measuring the average evoked response potential amplitude change for P100 at Baseline, 5 day and 1 month visits. ssVEP was utilized to measure changes in electrical biomarkers of the early visual response. Stimuli consisted of 50 trials of a black and white square oscillating at 18.75 Hz in the subject's central, bilateral, left, or right visual field for 2000 ms (200 total trials pseudorandomly interleaved) with inter-trial intervals of 2.5 seconds.

Measuring the average evoked response potential amplitude change for P100 at Baseline, 5 day and 1 month visits. ssVEP was utilized to measure changes in electrical biomarkers of the early visual response. Stimuli consisted of 50 trials of a black and white square oscillating at 18.75 Hz in the subject's central, bilateral, left, or right visual field for 2000 ms (200 total trials pseudorandomly interleaved) with inter-trial intervals of 2.5 seconds.

Measuring total psychosis symptoms score. PANSS is a clinician administered instrument which has 30 items measuring a range of symptoms which are rated on a 7-point scale (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, and 7=extreme). A total score ranges from 30-210 with higher scores indicate worsen symptoms. Subscales include, general, negative and positive symptom categories with higher scores indicate worsen symptoms. The range for the positive and negative Scales is 7-49, and the range for the general Psychopathology Scale is 16-112.

Measuring total psychosis symptoms score. PANSS is a clinician administered instrument which has 30 items measuring a range of symptoms which are rated on a 7-point scale (1=absent, 2=minimal, 3=mild, 4=moderate, 5=moderate severe, 6=severe, and 7=extreme). A total score ranges from 30-210 with higher scores indicate worsen symptoms. Subscales include, general, negative and positive symptom categories with higher scores indicate worsen symptoms. The range for the positive and negative Scales is 7-49, and the range for the general Psychopathology Scale is 16-112.

Measuring the percent correct of detected motion. Biological motion perception was assessed using point-light animations (12 dots on the head and major joints of the body) walking either rightward or leftward. The target animation was embedded in a number of random-moving noise dots (24, 48, or 72) to manipulate the difficulty level of the task. Participants were asked to indicate the direction that the animation was walking towards. The task lasted for about 4 minutes.

Measuring the percent correct of detected motion. Biological motion perception was assessed using point-light animations (12 dots on the head and major joints of the body) walking either rightward or leftward. The target animation was embedded in a number of random-moving noise dots (24, 48, or 72) to manipulate the difficulty level of the task. Participants were asked to indicate the direction that the animation was walking towards. The task lasted for about 4 minutes.

Emotional evoked related potential (ERP) measures were obtained using the IAPS, which consists of unpleasant, pleasant, and neutral scene stimuli. Scenes consisted of human threat, animal threat, erotica, romantic couples, people, families, and landscapes. During each experimental session, participants viewed each scene three times. Images were presented for 1000 ms and then followed by 3.5 s of a black screen with a small red dot as a fixation point.

Emotional evoked related potential (ERP) measures were obtained using the IAPS, which consists of unpleasant, pleasant, and neutral scene stimuli. Scenes consisted of human threat, animal threat, erotica, romantic couples, people, families, and landscapes. During each experimental session, participants viewed each scene three times. Images were presented for 1000 ms and then followed by 3.5 s of a black screen with a small red dot as a fixation point.

Velocity discrimination performance was determined using constant stimuli method. Participants asked to indicate the faster of the two gradients (drifting Gabor patches) presented sequentially for 300 ms with an inter-stimulus interval of 500ms 51.There were 9 velocity difference levels to modulate the difficulty of the task. 15 trials were presented at each difficulty level. Velocity discrimination thresholds, which corresponds to an accuracy level equivalent to 75% correct for each subject, calculated as an indicator of performance. This task session lasted for about 5 minutes.

Velocity discrimination performance was determined using constant stimuli method. Participants asked to indicate the faster of the two gradients (drifting Gabor patches) presented sequentially for 300 ms with an inter-stimulus interval of 500ms 51.There were 9 velocity difference levels to modulate the difficulty of the task. 15 trials were presented at each difficulty level. Velocity discrimination thresholds, which corresponds to an accuracy level equivalent to 75% correct for each subject, calculated as an indicator of performance. This task session lasted for about 5 minutes.

To assess visuospatial working memory participants were asked to identify and remember the location of the odd shape out of three shapes. The procedure was repeated with three new shapes following an interval. Participants were asked to respond by indicating where the odd shapes appeared, in the correct order of appearance. Two correct trials on each level led to progression to the next level where the item load was increased by one. The session was terminated when two trials on the same level were incorrect. The final score was calculated based on the performance on the highest level achieved (10 max) where at least one trial was passed. A higher score means better visual spatial memory capability (0-10) and the highest difficulty level achieved. This task lasted for 3-5 minutes.

To assess visuospatial working memory participants were asked to identify and remember the location of the odd shape out of three shapes. The procedure was repeated with three new shapes following an interval. Participants were asked to respond by indicating where the odd shapes appeared, in the correct order of appearance. Two correct trials on each level led to progression to the next level where the item load was increased by one. The session was terminated when two trials on the same level were incorrect. The final score was calculated based on the performance on the highest level achieved (10 max) where at least one trial was passed. A higher score means better visual spatial memory capability (0-10) and the highest difficulty level achieved. This task lasted for 3-5 minutes.

Measuring global functioning derived from patients symptoms, relationships and functioning in life. The higher the score, the better individual handles daily activities and lower symptoms experienced. 91-100 No symptoms. Superior functioning in a wide range of activities. 81-90 Absent or minimal symptoms, good functioning in all areas. 71-80 Symptoms are transient and expectable reactions to psychosocial stressors. 61-70 Some mild symptoms or some difficulty in functioning. 51-60 Moderate symptoms or moderate difficulty in functioning. 41-50 Serious symptoms or any serious impairment in functioning 31-40 Some impairment or major impairment in several areas, such as work or school, family relations, judgment, thinking, or mood. 21-30 Behavior is considerably influenced by delusions or hallucinations or serious impairment 11-20 Some danger of hurting self or others. 1-10 Persistent danger of severely hurting self or others. 0 Inadequate information

Measuring global functioning derived from patients symptoms, relationships and functioning in life. The higher the score, the better individual handles daily activities and lower symptoms experienced. 91-100 No symptoms. Superior functioning in a wide range of activities. 81-90 Absent or minimal symptoms, good functioning in all areas. 71-80 Symptoms are transient and expectable reactions to psychosocial stressors. 61-70 Some mild symptoms or some difficulty in functioning. 51-60 Moderate symptoms or moderate difficulty in functioning. 41-50 Serious symptoms or any serious impairment in functioning 31-40 Some impairment or major impairment in several areas, such as work or school, family relations, judgment, thinking, or mood. 21-30 Behavior is considerably influenced by delusions or hallucinations or serious impairment 11-20 Some danger of hurting self or others. 1-10 Persistent danger of severely hurting self or others. 0 Inadequate information

Measuring total depression scores, The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire which psychiatrists or trained mental health providers use to measure the severity of depressive episodes and or symptoms in patients with mood disorders. A higher score indicates worsen depression. The questionnaire includes questions on ten symptoms:Apparent sadness, Reported sadness, Inner tension, Reduced sleep, Reduced appetite, Concentration difficulties, Lassitude, Inability to feel, Pessimistic thoughts, Suicidal thoughts. Total used from scale indicates: 0 to 6: normal/symptom absent 7 to 19: mild depression 20 to 34: moderate depression 35 to 60: severe depression

Measuring total depression scores, The Montgomery-Åsberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire which psychiatrists or trained mental health providers use to measure the severity of depressive episodes and or symptoms in patients with mood disorders. A higher score indicates worsen depression. The questionnaire includes questions on ten symptoms:Apparent sadness, Reported sadness, Inner tension, Reduced sleep, Reduced appetite, Concentration difficulties, Lassitude, Inability to feel, Pessimistic thoughts, Suicidal thoughts. Total used from scale indicates: 0 to 6: normal/symptom absent 7 to 19: mild depression 20 to 34: moderate depression 35 to 60: severe depression

Inclusion Criteria: meet diagnostic criteria for schizophrenia, schizoaffective disorder, or psychotic bipolar disorder as verified by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV TR) and consensus clinical diagnosis; had no changes to relevant anti-psychotic medications for a period of 1 month prior to participation; had a sufficient level of English to allow participation. Exclusion Criteria: pregnant or breastfeeding women; Intelligence quotient <60 any major medical or neurologic diagnosis of substance abuse positive urine drug screen history of moderate-to-severe visual impairment secondary to glaucoma, cataract or macular degeneration serious medical illness or instability requiring hospitalization within the next year relevant skin allergies; metallic or electronic implants (e.g. pacemakers, brain stimulators).