Stimulating the inferior fronto-occipital fasciculus elicits complex visual hallucinations

Abstract

Complex visual hallucinations are vivid visual percepts (e.g. scenes, figures) that appear without an external stimulus. These percepts may be elicited during electrical brain stimulation (EBS) mapping, a procedure performed during evaluation and surgical treatment of patients with severe intractable focal epilepsy [1Selimbeyoglu A. Parvizi J. Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.Front Hum Neurosci. 2010; 4: 46https://doi.org/10.3389/fnhum.2010.00046Crossref PubMed Scopus (120) Google Scholar, 2Elliott B. Joyce E. Shorvon S. Delusions, illusions and hallucinations in epilepsy: 1. Elementary phenomena.Epilepsy Res. 2009; 85: 162-171https://doi.org/10.1016/j.eplepsyres.2009.03.018Crossref PubMed Scopus (69) Google Scholar, 3Andelman-Gur M.M. Gazit T. Andelman F. Kipervasser S. Kramer U. Neufeld M.Y. et al.Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.J Neurosurg. 2019; 133: 54-62https://doi.org/10.3171/2019.3.JNS183429Crossref PubMed Scopus (1) Google Scholar]. When evoked during EBS, these hallucinations usually involve mnemonic and affective content [[1]Selimbeyoglu A. Parvizi J. Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.Front Hum Neurosci. 2010; 4: 46https://doi.org/10.3389/fnhum.2010.00046Crossref PubMed Scopus (120) Google Scholar,[2]Elliott B. Joyce E. Shorvon S. Delusions, illusions and hallucinations in epilepsy: 1. Elementary phenomena.Epilepsy Res. 2009; 85: 162-171https://doi.org/10.1016/j.eplepsyres.2009.03.018Crossref PubMed Scopus (69) Google Scholar,[4]Gloor P. Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses.Brain. 1990; 113: 1673-1694https://doi.org/10.1093/brain/113.6.1673Crossref PubMed Scopus (308) Google Scholar], and are typically induced in the occipital and temporal lobes [[3]Andelman-Gur M.M. Gazit T. Andelman F. Kipervasser S. Kramer U. Neufeld M.Y. et al.Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.J Neurosurg. 2019; 133: 54-62https://doi.org/10.3171/2019.3.JNS183429Crossref PubMed Scopus (1) Google Scholar,[4]Gloor P. Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses.Brain. 1990; 113: 1673-1694https://doi.org/10.1093/brain/113.6.1673Crossref PubMed Scopus (308) Google Scholar] while only rarely in the frontal lobe regions [[3]Andelman-Gur M.M. Gazit T. Andelman F. Kipervasser S. Kramer U. Neufeld M.Y. et al.Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.J Neurosurg. 2019; 133: 54-62https://doi.org/10.3171/2019.3.JNS183429Crossref PubMed Scopus (1) Google Scholar,[5]Blanke O. Landis T. Seeck M. Electrical cortical stimulation of the human prefrontal cortex evokes complex visual hallucinations.Epilepsy Behav. 2000; 1: 356-361https://doi.org/10.1006/ebeh.2000.0109Abstract Full Text PDF PubMed Scopus (41) Google Scholar]. It has been suggested that these multifaceted visual phenomena arise from the activation of widely distributed neural networks [1Selimbeyoglu A. Parvizi J. Electrical stimulation of the human brain: perceptual and behavioral phenomena reported in the old and new literature.Front Hum Neurosci. 2010; 4: 46https://doi.org/10.3389/fnhum.2010.00046Crossref PubMed Scopus (120) Google Scholar, 2Elliott B. Joyce E. Shorvon S. Delusions, illusions and hallucinations in epilepsy: 1. Elementary phenomena.Epilepsy Res. 2009; 85: 162-171https://doi.org/10.1016/j.eplepsyres.2009.03.018Crossref PubMed Scopus (69) Google Scholar, 3Andelman-Gur M.M. Gazit T. Andelman F. Kipervasser S. Kramer U. Neufeld M.Y. et al.Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.J Neurosurg. 2019; 133: 54-62https://doi.org/10.3171/2019.3.JNS183429Crossref PubMed Scopus (1) Google Scholar]. Yet, the specific white matter tracts involved in these networks remain unclear, especially in the frontal regions. Here we describe two patients who experienced complex visual hallucinations during electrostimulation of their orbito-frontal white matter tracts. By combining EBS findings with generalized Q-sampling imaging, we identify the inferior fronto-occipital fasciculus (IFOF) as the origin of these responses. We describe two patients with epilepsy in whom frontal EBS resulted in complex visual hallucinations. Patient 1 is a 35-year-old female, with epilepsy onset at the age of 26. Patient 2 is a 28-year-old male, with intractable epilepsy from the age of 14. Surface video-EEG suggested right fronto-temporal ictal activity for patient 1, and left frontal seizure onset for patient 2. High-resolution brain MRI scans (T1, T2, and diffusion-weighted; 1mm slices) were obtained on a 3T Scanner; no structural abnormalities were observed. Both patients underwent invasive EEG monitoring using depth electrodes to delineate their epileptic foci. Each electrode had six to eight contacts, with an exposed surface of 1.3 mm2 and an intercontact distance of 5 mm [AD-tech, Racine, WI, USA]. Depth electrodes were implanted according clinical criteria aimed at identifying the seizure focus. Patient 1 underwent two implantations in the frontal, temporal, and occipital lobes bilaterally. Patient 2 underwent bilateral frontal and left temporo-parietal implantation. Invasive monitoring located the seizure focus in the right posterior parahippocampal gyrus in patient 1, and a supplementary motor area focus in patient 2. To perform pre-surgical functional mapping, EBS was conducted using Nicolet Cortical Stimulator [Natus, Middleton, WI, USA]. Alternating bipolar current was generated between all adjacent contacts, using the following parameters: 300 μsec wave width, 50 Hz frequency, 5 sec duration, and 1–4 mA current amplitude. Sham trials were occasionally introduced (with 0 mA) to test placebo effect, with no subsequent response. In both patients, EBS yielded verbal, motor, and sensory responses according to the expected functional anatomy. In addition, complex visual hallucinations were reported, as detailed in Table 1. In patient 1, stimulation of white matter tracts in the orbito-frontal area bilaterally and in the anterior right parahippocampal region evoked visual hallucinations, such as: “I see a scene, a memory from 12 years ago in Thailand, me and my divorcee are riding a “Tuk-Tuk”; I see the merchants in the market, the stands”. In patient 2, stimulation of white-matter within the left orbito-frontal region provoked a visual hallucination: “I see my wife, her face, she is worried, she is in the labor room”. These stimulations were not accompanied by epileptic after-discharges or seizures.Table 1Complex visual hallucinations induced during EBS.EBS target siteResponseMNI coordinatesCurrent (mA)Patient 1Left orbito-frontal white matter (Fig. 1B)“I see the face of my deceased mother”(-21,50,-8)4Right orbito-frontal white matter (Fig. 1A)“I see a scene, a memory from 12 years ago in Thailand, me and my divorcee are riding a “Tuk-Tuk”, I see the merchants in the market, the stands”(20,38,0)3“I see a picture of an animal, the animal is vomiting or defecating, maybe a horse”(26,38,0)4“I feel I am at a TV show, I see the newscaster and the audience”(31,38,0)3“I see an orchard, many people around, someone is telling me what to do, he is holding a microphone”(37,38,0)4Right anterior parahippocampal region (white matter) (Fig. 1A)“I see a painted picture, an animated figure”(40,-14,-22)2“I see a big brown dog”(40,-14,-22)4“I see the entrance to a specific neighborhood” (later on, she reported this neighborhood is close to the cemetery where her mother is buried)(40,-14,-22)4“I see a figure, a woman, I know her but I can’t remember how, probably from my childhood”(40,-14,-22)4Patient 2Left orbito-frontal white matter (Fig. 1C)“I see my wife, her face, she is worried, she is in the labor room”(-18,40,-6)4 Open table in a new tab Since the hallucinations were mainly induced in the white matter of the orbito-frontal area, and based on the known pathway of the IFOF terminating in these particular regions [[5]Blanke O. Landis T. Seeck M. Electrical cortical stimulation of the human prefrontal cortex evokes complex visual hallucinations.Epilepsy Behav. 2000; 1: 356-361https://doi.org/10.1006/ebeh.2000.0109Abstract Full Text PDF PubMed Scopus (41) Google Scholar], we hypothesized that the IFOF was stimulated in both patients. To test our hypothesis, the IFOF was reconstructed [Fig. 1] using diffusion spectrum imaging Studio software (available from: http://dsi-studio.labsolver.org) and generalized Q-sampling imaging technique, with the following parameters: 1.6 threshold value, 70° angular threshold, and 300 mm maximum length. To reconstruct the IFOF, frontal and occipital coronal slices were selected as regions of interest, as previously described [[6]Sarubbo S. De Benedictis A. Maldonado I.L. Basso G. Duffau H. Frontal terminations for the inferior fronto-occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-component bundle.Brain Struct Funct. 2013; 218: 21-37https://doi.org/10.1007/s00429-011-0372-3Crossref PubMed Scopus (193) Google Scholar]. Afterward, the locations of the stimulations eliciting complex visual hallucinations were co-registered with an anatomical T2-weighted-flair volume in the same neuroanatomical space [Fig. 1]. We found that all electrodes that elicited complex visual hallucinations in both patients were located within the borders of the IFOF, identifying the IFOF as the origin of these responses. Our findings provide unique reports of rare complex visual hallucinations induced by electrostimulation of white-matter tracts within the orbito-frontal region, identified as the IFOF. Both patients in our study described seeing vivid scenes, some with strong emotional and mnemonic content, similar to responses previously reported with stimulation of temporal and occipito-temporal sites [[4]Gloor P. Experiential phenomena of temporal lobe epilepsy. Facts and hypotheses.Brain. 1990; 113: 1673-1694https://doi.org/10.1093/brain/113.6.1673Crossref PubMed Scopus (308) Google Scholar]. Our results support and extend previous reports of complex visual hallucinations evoked during EBS of the frontal lobes. Blanke et al. [[5]Blanke O. Landis T. Seeck M. Electrical cortical stimulation of the human prefrontal cortex evokes complex visual hallucinations.Epilepsy Behav. 2000; 1: 356-361https://doi.org/10.1006/ebeh.2000.0109Abstract Full Text PDF PubMed Scopus (41) Google Scholar] described complex visual hallucinations induced during electrostimulation of the left prefrontal cortex in two patients. The authors concluded that the prefrontal cortex is involved in mnemonic and visual processing. Previously [[3]Andelman-Gur M.M. Gazit T. Andelman F. Kipervasser S. Kramer U. Neufeld M.Y. et al.Spatial distribution and hemispheric asymmetry of electrically evoked experiential phenomena in the human brain.J Neurosurg. 2019; 133: 54-62https://doi.org/10.3171/2019.3.JNS183429Crossref PubMed Scopus (1) Google Scholar], we presented a patient in whom complex visual hallucinations were elicited while stimulating the cortical surfaces of the right inferior, middle, and superior frontal gyri. The current study further extends our previous report, by showing that complex vivid visual responses are induced by direct stimulation of the IFOF, possibly due to its ability to connect between widely distributed cortical regions [[7]Catani M. Thiebaut de Schotten M. A diffusion tensor imaging tractography atlas for virtual in vivo dissections.Cortex. 2008; 44: 1105-1132https://doi.org/10.1016/j.cortex.2008.05.004Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar]. Our report sheds light on a novel integrative visual function of the IFOF. The IFOF is a ventral white matter tract that connects the occipital and the frontal lobes [[7]Catani M. Thiebaut de Schotten M. A diffusion tensor imaging tractography atlas for virtual in vivo dissections.Cortex. 2008; 44: 1105-1132https://doi.org/10.1016/j.cortex.2008.05.004Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar], and interestingly seems to exist only in humans [6Sarubbo S. De Benedictis A. Maldonado I.L. Basso G. Duffau H. Frontal terminations for the inferior fronto-occipital fascicle: anatomical dissection, DTI study and functional considerations on a multi-component bundle.Brain Struct Funct. 2013; 218: 21-37https://doi.org/10.1007/s00429-011-0372-3Crossref PubMed Scopus (193) Google Scholar, 7Catani M. Thiebaut de Schotten M. A diffusion tensor imaging tractography atlas for virtual in vivo dissections.Cortex. 2008; 44: 1105-1132https://doi.org/10.1016/j.cortex.2008.05.004Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar, 8Duffau H. Stimulation mapping of white matter tracts to study brain functional connectivity.Nat Rev Neurol. 2015; 11: 255-265https://doi.org/10.1038/nrneurol.2015.51Crossref PubMed Scopus (197) Google Scholar]. Although the IFOF functions are not fully known, previous studies have shown that it is involved in semantic processing [[9]Moritz-Gasser S. Herbet G. Duffau H. Mapping the connectivity underlying multimodal (verbal and non-verbal) semantic processing: a brain electrostimulation study.Neuropsychologia. 2013; 51: 1814-1822https://doi.org/10.1016/j.neuropsychologia.2013.06.007Crossref PubMed Scopus (130) Google Scholar], reading, attention [[7]Catani M. Thiebaut de Schotten M. A diffusion tensor imaging tractography atlas for virtual in vivo dissections.Cortex. 2008; 44: 1105-1132https://doi.org/10.1016/j.cortex.2008.05.004Abstract Full Text Full Text PDF PubMed Scopus (1031) Google Scholar,[8]Duffau H. Stimulation mapping of white matter tracts to study brain functional connectivity.Nat Rev Neurol. 2015; 11: 255-265https://doi.org/10.1038/nrneurol.2015.51Crossref PubMed Scopus (197) Google Scholar], and visual processing, such as face recognition [[10]Thomas C. Avidan G. Humphreys K. Jung K. Gao F. Behrmann M. Reduced structural connectivity in ventral visual cortex in congenital prosopagnosia.Nat Neurosci. 2009; 12: 29-31https://doi.org/10.1038/nn.2224Crossref PubMed Scopus (233) Google Scholar]. Our study supports the role of the IFOF in visual processing as previously described [[10]Thomas C. Avidan G. Humphreys K. Jung K. Gao F. Behrmann M. Reduced structural connectivity in ventral visual cortex in congenital prosopagnosia.Nat Neurosci. 2009; 12: 29-31https://doi.org/10.1038/nn.2224Crossref PubMed Scopus (233) Google Scholar]. Moreover, since the visual hallucinations induced in our patients often contained strong affective and mnemonic attributes, we suggest that the IFOF is part of a network integrating complex visual, mnemonic, and emotional content. Taken together, these findings suggest that electrical stimulation mapping of cortical functions should be evaluated not merely based on the localized site of stimulation, but also taking into consideration the connecting pathways that together may uncover the networks subserving the specific mapped cortical function. None.

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