Transcranial Direct Current Stimulation in the Treatment of Visual Hallucinations in Charles Bonnet Syndrome: A Randomized Placebo-Controlled Crossover Trial.

OBJECTIVE: To investigate the potential therapeutic benefits and tolerability of inhibitory transcranial direct current stimulation (tDCS) on the remediation of visual hallucinations in Charles Bonnet syndrome (CBS). DESIGN: Randomized, double-masked, placebo-controlled crossover trial. PARTICIPANTS: Sixteen individuals diagnosed with CBS secondary to visual impairment caused by eye disease experiencing recurrent visual hallucinations. INTERVENTION: All participants received 4 consecutive days of active and placebo cathodal stimulation (current density: 0.29 mA/cm2) to the visual cortex (Oz) over 2 defined treatment weeks, separated by a 4-week washout period. MAIN OUTCOME MEASURES: Ratings of visual hallucination frequency and duration following active and placebo stimulation, accounting for treatment order, using a 2 × 2 repeated-measures model. Secondary outcomes included impact ratings of visual hallucinations and electrophysiological measures. RESULTS: When compared with placebo treatment, active inhibitory stimulation of visual cortex resulted in a significant reduction in the frequency of visual hallucinations measured by the North East Visual Hallucinations Interview, with a moderate-to-large effect size. Impact measures of visual hallucinations improved in both placebo and active conditions, suggesting support and education for CBS may have therapeutic benefits. Participants who demonstrated greater occipital excitability on electroencephalography assessment at the start of treatment were more likely to report a positive treatment response. Stimulation was found to be tolerable in all participants, with no significant adverse effects reported, including no deterioration in preexisting visual impairment. CONCLUSIONS: Findings indicate that inhibitory tDCS of visual cortex may reduce the frequency of visual hallucinations in people with CBS, particularly individuals who demonstrate greater occipital excitability prior to stimulation. tDCS may offer a feasible intervention option for CBS with no significant side effects, warranting larger-scale clinical trials to further characterize its efficacy.

Risk factors for early psychosis in PD: insights from the Parkinson's Progression Markers Initiative.

BACKGROUND: Parkinson's Disease (PD) psychosis refers to the spectrum of illusions, formed hallucinations and delusions that occur in PD. Visual hallucinations and illusions are thought to be caused by specific cognitive and higher visual function deficits and patients who develop such symptoms early in the disease course have greater rates of cognitive decline and progression to dementia. To date, no studies have investigated whether such deficits are found prior to the onset of PD psychosis. METHOD: Here we compare baseline cognitive, biomarker (structural imaging and cerebrospinal fluid) and other PD psychosis risk factor data in patients who go on to develop illusions or hallucinations within 3-4 years of follow-up in the Parkinson's Progression Markers Initiative cohort of newly diagnosed PD. RESULTS: Of n=423 patients with PD, n=115 (27%) reported predominantly illusions with the median time of onset at 19.5 months follow-up. At study entry these patients had reduced CSF amyloid Aß1-42, lower olfaction scores, higher depression scores and increased REM sleep behaviour disorder symptoms compared to patients without early onset PD psychosis but no differences in cognitive, higher visual or structural imaging measures. A subset of patients with early onset formed hallucinations (n=21) had reduced higher visual function at baseline, cortical thinning in parietal, occipital and frontal cortex and reduced hippocampal volume. CONCLUSIONS: The findings suggest early onset illusions and formed hallucinations are linked to amyloid pathology in PD and point to a difference in the underlying pathophysiological mechanism of illusions and formed hallucinations, with implications for their respective links to future cognitive decline.

Are stroke survivors with delirium at higher risk of post-stroke dementia? Current evidence and future directions.

OBJECTIVES: The idea that delirium is a risk factor for dementia, broadly defined, is derived from heterogeneous patient samples. We reviewed available evidence as to whether stroke survivors who developed delirium during the acute phase of treatment are at a higher prospective risk of incident post-stroke cognitive impairment or dementia. DESIGN: We searched 8721 records in the Cochrane database for reviews or protocols dealing with the study objective, Medline, EMBASE, PsycInfo and CINAHL for observational studies in the general adult population and PubMed for in-process articles. Additional searches of the reference lists of retrieved articles were also undertaken. Qualitative syntheses and meta-analysis were conducted according to conventional guidelines. RESULTS: Twelve relevant articles were fully appraised. Four out of these studies, comprising 743 stroke survivors, including 199 with delirium, met criteria for qualitative syntheses. Overall, the studies presented low to moderate level evidence suggesting an association between post-stroke delirium and dementia. CONCLUSIONS: There is a need for further studies to investigate the association of post-stroke delirium and dementia using well-defined cohorts of patients and controlling for factors such as pre-stroke cognition, stroke severity and location and the presence of persistent delirium. Such studies will help understand the place of delirium identification and prevention in reducing the risk of dementia after stroke. © 2016 The Authors. International Journal of Geriatric Psychiatry Published by John Wiley & Sons Ltd.

Art and the brain: a view from dementia.

OBJECTIVE: Art making encompasses a range of perceptual and cognitive functions involving widely distributed brain systems. The dementias impact on these systems in different ways, raising the possibility that each dementia has a unique artistic signature. DESIGN: Here we use a review of the visual art of 14 artists with dementia (five Alzheimer's disease, seven fronto-temporal dementia and two dementia with Lewy bodies) to further our understanding of the neurobiological constituents of art production and higher artistic function. RESULTS: Artists with Alzheimer's disease had prominent changes in spatial aspects of their art and attributes of colour and contrast. These qualities were preserved in the art of fronto-temporal dementia, which was characterised by perseverative themes and a shift towards realistic representation. The art of dementia with Lewy Bodies was characterised by simple, bizarre content. CONCLUSIONS: The limitations of using visual aspects of individual artworks to infer the impact of dementia on art production are discussed with the need for a wider perspective encompassing changes in cognition, emotion, creativity and artistic personality. A novel classificatory scheme is presented to help characterise neural mechanisms of higher artistic functions in future studies.

A novel method for reducing the effect of tonic muscle activity on the gamma band of the scalp EEG.

Neural oscillations in the gamma band are of increasing interest, but separating them from myogenic electrical activity has proved difficult. A novel algorithm has been developed to reduce the effect of tonic scalp and neck muscle activity on the gamma band of the EEG. This uses mathematical modelling to fit individual muscle spikes and then subtracts them from the data. The method was applied to the detection of motor associated gamma in two separate groups of eight subjects using different sampling rates. A reproducible increase in high gamma (65-85 Hz) magnitude occurred immediately after the motor action in the left central area (p = 0.02 and p = 0.0002 for the two cohorts with individually optimized algorithm parameters, compared to p = 0.03 and p = 0.16 before correction). Whilst the magnitude of this event-related gamma synchronisation was not reduced by the application of the EMG reduction algorithm, the baseline left central gamma magnitude was significantly reduced by an average of 23 % with a faster sampling rate (p < 0.05). In comparison, at left and right temporo-parietal locations the gamma amplitude was reduced by 60 and 54 % respectively (p < 0.05). The reduction of EMG contamination by fitting and subtraction of individual spikes shows promise as a method of improving the signal to noise ratio of high frequency neural oscillations in scalp EEG.

PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans.

The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight. However, in the current 'obesogenic' human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans. Here we show, using functional magnetic resonance imaging, that peptide YY3-36 (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.

The primary visual cortex, and feedback to it, are not necessary for conscious vision.

A compelling single case report of visual awareness (visual qualia) without primary visual cortex would be sufficient to refute the hypothesis that the primary visual cortex and the back-projections to it are necessary for conscious visual experience. In a previous study, we emphasized the presence of crude visual awareness in Patient G.Y., with a lesion of the primary visual cortex, who is aware of, and able to discriminate, fast-moving visual stimuli presented to his blind field. The visual nature of Patient G.Y.'s blind field experience has since been questioned and it has been suggested that the special circumstances of repeated testing over decades may have altered Patient G.Y.'s visual pathways. We therefore sought new evidence of visual awareness without primary visual cortex in patients for whom such considerations do not apply. Three patients with hemianopic field defects (Patient G.N. and Patient F.B. with MRI confirmed primary visual cortex lesions, Patient C.G. with an inferred lesion) underwent detailed psychophysical testing in their blind fields. Visual stimuli were presented at different velocities and contrasts in two- and four-direction discrimination experiments and the direction of motion and awareness reported using a forced-choice paradigm. Detailed verbal reports were also obtained of the nature of the blind field experience with comparison of the drawings of the stimulus presented in the blind and intact fields, where possible. All three patients reported visual awareness in their blind fields. Visual awareness was significantly more likely when a moving stimulus was present compared to no stimulus catch trials (P < 0.01 for each subject). Psychophysical performance in Patient F.B. and Patient G.N. was consistent with the Riddoch syndrome, with higher levels of visual awareness for moving compared to static stimuli (P < 0.001) and intact direction discrimination (P < 0.0001 for two- and four-direction experiments). Although the blind field experience of all three subjects was degraded, it was clearly visual in nature. We conclude that the primary visual cortex or back-projections to it are not necessary for visual awareness.

Neural changes following cognitive behaviour therapy for psychosis: a longitudinal study.

A growing body of evidence demonstrates that persistent positive symptoms, particularly delusions, can be improved by cognitive behaviour therapy for psychosis. Heightened perception and processing of threat are believed to constitute the genesis of delusions. The present study aimed to examine functional brain changes following cognitive behaviour therapy for psychosis. The study involved 56 outpatients with one or more persistent positive distressing symptoms of schizophrenia. Twenty-eight patients receiving cognitive behaviour therapy for psychosis for 6-8 months in addition to their usual treatment were matched with 28 patients receiving treatment as usual. Patients' symptoms were assessed by a rater blind to treatment group, and they underwent functional magnetic resonance imaging during an affect processing task at baseline and end of treatment follow-up. The two groups were comparable at baseline in terms of clinical and demographic parameters and neural and behavioural responses to facial and control stimuli. The cognitive behaviour therapy for psychosis with treatment-as-usual group (22 subjects) showed significant clinical improvement compared with the treatment-as-usual group (16 subjects), which showed no change at follow-up. The cognitive behaviour therapy for psychosis with treatment-as-usual group, but not the treatment-as-usual group, showed decreased activation of the inferior frontal, insula, thalamus, putamen and occipital areas to fearful and angry expressions at treatment follow-up compared with baseline. Reduction of functional magnetic resonance imaging response during angry expressions correlated directly with symptom improvement. This study provides the first evidence that cognitive behaviour therapy for psychosis attenuates brain responses to threatening stimuli and suggests that cognitive behaviour therapy for psychosis may mediate symptom reduction by promoting processing of threats in a less distressing way.

Atlasing location, asymmetry and inter-subject variability of white matter tracts in the human brain with MR diffusion tractography.

The purpose of this study is to create a white matter atlas of the human brain using diffusion tensor imaging (DTI) tractography and to describe the constant and variable features of the major pathways. DTI was acquired from 40 healthy right-handed adults and reconstructed tracts mapped within a common reference space (MNI). Group effect maps of each tract defined constant anatomical features while overlap maps were generated to study inter-subject variability and to compare DTI derived anatomy with a histological atlas. Two patients were studied to assess the localizing validity of the atlas. The DTI-derived maps are overall consistent with a previously published histological atlas. A statistically significant leftward asymmetry was found for the volume and number of streamlines of the cortico-spinal tract and the direct connections between Broca's and Wernicke's territories (long segment). A statistically significant rightward asymmetry was found for the inferior fronto-occipital fasciculus and the fronto-parietal connections (anterior segment) of the arcuate fasciculus. Furthermore, males showed a left lateralization of the fronto-temporal segment of the arcuate fasciculus (long segment), while females had a more bilateral distribution. In two patients with brain lesions, DTI was acquired and tractography used to show that the tracts affected by the lesions were correctly identified by the atlas. This study suggests that DTI-derived maps can be used together with a previous histological atlas to establish the relationship of focal lesions with nearby tracts and improve clinico-anatomical correlation.

A century of prosopometamorphopsia studies.

Prosopometamorphopsia is an extremely rare disorder of visual perception characterised by facial distortions. We here review 81 cases (eight new ones and 73 cases published over the past century) to shed light on the perception of face gestalts. Our analysis indicates that the brain systems underlying the perception of face gestalts have genuine network properties, in the sense that they are widely disseminated and built such that spatially normal perception of faces can be maintained even when large parts of the network are compromised. We found that bilateral facial distortions were primarily associated with right-sided and bilateral occipital lesions, and unilateral facial distortions with lesions ipsilateral to the distorted hemifield and with the splenium of the corpus callosum. We also found tentative evidence for the involvement of the left frontal regions in the fusing of vertical hemi-images of faces, and of right parietal regions in the fusing of horizontal hemi-images. Evidence supporting the remarkable adaptability of the network comes from the relatively high recovery rates that we found, from the ipsilateral hemifield predominance of hemi-prosopometamorphopsia, and from a phenomenon called cerebral asthenopia (heightened visual fatigability) which points to the dynamic nature of compensatory mechanisms maintaining normal face perception, even in chronic cases of prosopometamorphopsia. Finally, our analysis suggests that specialised networks for the representation of face gestalts in familiar-versus-unfamiliar faces and for own-versus-other face may be present, although this is in need of further study.

Resting-state EEG alpha/theta ratio related to neuropsychological test performance in Parkinson's Disease.

OBJECTIVE: To determine possible associations of hemispheric-regional alpha/theta ratio (α/θ) with neuropsychological test performance in Parkinson's Disease (PD) non-demented patients. METHODS: 36 PD were matched to 36 Healthy Controls (HC). The α/θ in eight hemispheric regions was computed from the relative power spectral density of the resting-state quantitative electroencephalogram (qEEG). Correlations between α/θ and performance in several neuropsychological tests were conducted, significant findings were included in a moderation analysis. RESULTS: The α/θ in all regions was lower in PD than in HC, with larger effect sizes in the posterior regions. Right parietal, and right and left occipital α/θ had significant positive correlations with performance in Judgement of Line Orientation Test (JLOT) in PD. Adjusted moderation analysis indicated that right, but not left, occipital α/θ influenced the JLOT performance related to PD. CONCLUSIONS: Reduction of the occipital α/θ, in particular on the right side, was associated with visuospatial performance impairment in PD. SIGNIFICANCE: Visuospatial impairment in PD, which is highly correlated with the subsequent development of dementia, is reflected in α/θ in the right posterior regions. The right occipital α/θ may represent a useful qEEG marker for evaluating the presence of early signs of cognitive decline in PD and the subsequent risk of dementia.

Disorders of visual perception.

Visual perceptual disorders are often presented as a disparate group of neurological deficits with little consideration given to the wide range of visual symptoms found in psychiatric and neurodevelopmental disease. Here, the authors attempt a functional anatomical classification of all disorders linked to visual perception, whatever the clinical context in which they arise, including those disorders that bridge vision, emotion, memory, language and action. Guided by clinical and neuroimaging evidence, visual perceptual disorders are classified by the functional anatomical networks likely to be involved and the class of underlying dysfunction, whether topological (a localised deficit or region of hyperfunction) or hodological (a disconnection or hyperconnection). The wider perspective forces us to consider what visual functions underlie a range of symptoms sidelined by previous classificatory schemes and helps generate novel hypotheses for further research in the area.

Visual processing, social cognition and functional outcome in schizophrenia.

Visual processing deficits are well recognised in schizophrenia and have potentially important clinical implications. First, the pattern of deficits for different visual tasks may help understand the underlying pathophysiology of the visual dysfunction. Second, several studies report deficits correlating with functional outcomes, suggesting that outcome improvement is possible through visual remediation strategies. We investigated these issues in a group of 64 schizophrenia patients and matched controls with a battery of visual tasks targeting different points along the visual pathways and by examining direct and indirect relationships (via a potential mediator) of such deficits to functional outcome. The schizophrenia group was significantly worse on the visual tasks overall, with the deficit constant for low- and high-level processing. Zero-order correlations suggested minimal association between vision and outcome, however, correlations between three visual tasks and 'social perceptual' ability were found which in turn correlated with functional outcome; path analysis confirmed a significant but small and indirect effect of 'biological motion' processing ability on functional outcome mediated by 'social perception'. In conclusion, the pathophysiology of visual dysfunction affects low- and high-level visual areas similarly and the relationship between deficits and outcome is small and indirect.

Drug and Disease Effects in Parkinson's Psychosis: Revisiting the Role of Dopamine.

BACKGROUND: Levodopa and dopamine agonists (dopamine replacement therapy [DRT]) are implicated in Parkinson's disease psychosis (PDP), but the relationship between DRT and neurotransmitter dysfunction inherent to PD remains unclear. OBJECTIVES: To examine the relationship between baseline striatal dopamine transporter (DAT) binding in drug-naïve idiopathic PD, introduction of DRT, or dose change and incident early-onset PDP. METHODS: Baseline DAT binding was compared between patients with and without incident psychosis (defined here as hallucinations or delusions), controlling for age, sex, baseline cognition, and prospective DRT in the Parkinson's Progression Markers Initiative cohort. Incident illusions were not considered psychosis symptoms. RESULTS: Of 386 patients, 30 (8%) developed PDP (predominantly hallucinations, mean onset 42 months) and 355 (92%) had either no PDP symptoms (mean follow-up 64 months) or reported illusions only (111/355, 31%). Incident PDP was associated with reduced baseline striatal DAT binding, controlling for confounders (F 1,377 = 10.9; P = 0.001), but not with a specific DRT regime. A total of 6 patients developed PDP when DRT free. There was no suggestion that PDP onset was coincident with starting levodopa or levodopa dose increase. Incident illusions were not associated with reduced DAT binding. CONCLUSION: The findings highlight the role of disease-related dopamine mechanisms in the pathophysiology of hallucinations in Parkinson's disease alongside medication. It remains to be determined how dopamine mechanisms, medication, and other neurotransmitter systems implicated in PDP interact.

Hallucinations and other psychotic experiences across diagnoses: A comparison of phenomenological features.

Although psychotic experiences are prevalent across many psychiatric, neurological, and medical disorders, investigation of these symptoms has largely been restricted to diagnostic categories. This study aims to examine phenomenological similarities and differences across a range of diagnoses. We assessed frequency, severity and phenomenology of psychotic experiences in 350 outpatients including; participants with schizophrenia spectrum disorders, hearing impairment, Parkinson's disease, Lewy Body Dementia, Alzheimer's disease, visual impairment, posttraumatic stress disorder, borderline personality disorder, and participants with recent major surgery. Psychotic phenomena were explored between these groups using the Questionnaire for Psychotic Experiences (QPE). Participants with major psychiatric disorders reported a combination of several psychotic experiences, and more severe experiences compared to all other disorders. Participants with recent major surgery or visual impairment experienced isolated visual hallucinations. Participants with hearing impairment reported isolated auditory hallucinations, whereas the neurodegenerative disorders reported visual hallucinations, occasionally in combination with hallucinations in another modality or delusions. The phenomenology between neurodegenerative disorders, and within major psychiatric disorders showed many similarities. Our findings indicate that the phenomenology of psychotic experiences is not diagnosis specific, but may rather point to the existence of various subtypes across diagnoses. These subtypes could have a different underlying etiology requiring specific treatment.

Visual hallucinations in eye disease.

PURPOSE OF REVIEW: The literature related to visual hallucinations in ophthalmological settings from 2007 to 2008 is presented as a review of recent developments and trends. RECENT FINDINGS: Acuity, contrast sensitivity, age and sex emerge as significant and consistent risk factors for visual hallucinations, together with new evidence to suggest that up to 40% of patients have long-term hallucinations. Scotoma size and specific eye pathology do not influence hallucination risk. Induced hallucinations in normal individuals provide a model for those in eye disease, revealing a shift in thalamocortical circuitry and neurophysiological links to states of drowsy wakefulness. Serotonergic therapy emerges as a potential treatment. Two ophthalmological interventions are added to the list of procedures provoking hallucinations. Historical accounts of Charles Bonnet, his syndrome and two novel visual syndromes highlight ongoing difficulties of case definition and the wider clinical context in which visual hallucinations occur. SUMMARY: Current research into visual hallucination is predominantly ophthalmology-led, with increasing recognition of the phenomena, their prevalence and prognosis within the specialty. Deafferentation remains the best available pathophysiological account, although it fails to explain the absence of hallucinations in the majority of patients with eye disease. Whether hallucinations require treatment and, if so, what that treatment should be remains unclear.

Neural and behavioural responses to threat in men with a history of serious violence and schizophrenia or antisocial personality disorder.

BACKGROUND: Contemporary theories and evidence implicate defective emotion regulation in violent behaviour. The two psychiatric illnesses most implicated in violence are schizophrenia and antisocial personality disorder (APD). This study examined behavioural and brain abnormalities in violent men with schizophrenia or APD during anticipatory fear. METHOD: Fifty-three men [14 non-violent healthy controls, 13 with schizophrenia and a history of serious violence (VSZ), 13 with schizophrenia without a history of violence (SZ), 13 with APD and a history of serious violence] underwent blood-oxygenation-level-dependent fMRI during an experiment involving repeated presentations of 'safe' and 'threat of electric shock' conditions and provided ratings of shock anticipation and fear. Schizophrenia patients did not have co-morbid APD. RESULTS: VSZ participants reported the highest, and APD participants the lowest, level of shock anticipation and fear, with intermediate ratings by SZ and healthy participants. The violent, relative to non-violent, groups showed altered activity modulation in occipital and temporal regions, from early to latter parts of threat periods. Additionally, VSZ patients displayed exaggerated whereas APD patients showed attenuated thalamic-striatal activity during latter threat periods. CONCLUSIONS: Aberrant activity in occipital and temporal regions when exposed to sustained visual threat cues is associated with a predisposition to violence in both schizophrenia and APD. This common biological deficit, however, appears to arise from dissimilar behavioural mechanisms related to differences in the strength of aversive conditioning and behavioural response to sustained threat cues (enhanced in VSZ; attenuated in APD), also reflected in opposite patterns of alternations in thalamic-striatal activity, in these two disorders.

Decomposing the neural correlates of antisaccade eye movements using event-related FMRI.

The antisaccade task is a model of the conflict between an unwanted reflexive response (which must be inhibited) and a complex volitional response (which must be generated). The present experiment aimed to investigate separately the neural correlates of these cognitive components using a delayed saccade paradigm to dissociate saccade inhibition from generation. Seventeen healthy volunteers completed event-related functional magnetic resonance imaging at 1.5 T during saccades to and away from a peripheral visual target (prosaccades and antisaccades, respectively). Saccades were requested in response to an auditory go signal on average 12 s after peripheral target appearance. It was found that the right supramarginal gyrus showed significantly greater activation during the inhibition phase than the generation phase of the paradigm for both antisaccade and prosaccade trials, suggesting a role in saccade inhibition or stimulus detection. On the other hand, the right lateral frontal eye field and bilateral intraparietal sulcus showed evidence of selective involvement in antisaccade generation. Ventrolateral and dorsolateral prefrontal cortices showed comparable levels of activation in both phases of the task. These areas likely fulfill a more general supervisory role in the volitional control of eye movements, such as stimulus appraisal, task set, and decision making.

Perceived color of hallucinations in the Charles Bonnet Syndrome is related to residual color contrast sensitivity.

BACKGROUND: We sought to determine whether the change in cortical excitability secondary to deafferentation in patients with Charles Bonnet Syndrome (CBS) who hallucinate in a predominant color or combination of colors is related to an alteration in color contrast thresholds and whether the change is specific to the color of the hallucination. METHODS: We prospectively categorized each patient's hallucinations using the Institute of Psychiatry Visual Hallucinations Interview. We measured color contrast thresholds with a computerized test designed to assess red-green and blue-yellow color confusion axes against a background of luminance noise. We calculated the ratio of red-green threshold to blue-yellow threshold (R-G/B-Y ratio) for each patient. Because central vision was impaired in all patients, we used a sectoral annular stimulus that projected to the retina at 12.5 degrees eccentricity. RESULTS: There were 10 patients with age-related macular degeneration and CBS who were hallucinating in a predominant color or combination of colors at the time of recruitment. Patients hallucinating in red, green, or a combination of red and green had R-G/B-Y ratios of less than 1.0 (n = 5). Patients hallucinating in blue, yellow, or a combination of blue and yellow had R-G/B-Y ratios of greater than 1.0 (n = 2). Patients hallucinating in purple had ratios between the red-green and blue-yellow hallucinators (n = 2). The 1 patient hallucinating in white had the lowest thresholds for red-green and blue-yellow confusion axes. Comparing the R-G/B-Y ratios for the "red/green hallucinators" and "blue/yellow hallucinators" returned a significant result with Fisher's exact test (P = 0.047, n = 7). CONCLUSIONS: Deafferentation and secondary cortical hyperexcitability in CBS have a correlate in psychophysical threshold. This change in sensitivity relates specifically to the hallucinated color axis rather than across all colors. This is the first published evidence for cerebral hyperexcitability leading to a decrease in color contrast thresholds.

The hodology of hallucinations.

The hodotopic framework is a recent revision of Geschwind's disconnection paradigm incorporating advances in functional and white matter imaging. Its intention is to help clinico-pathological correlations across a range of neurological and psychiatric conditions and generate novel research questions. Here I consider hallucinations within this framework. The paper is divided into three parts. The first reviews the auditory and visual hallucination literature from the dual perspectives of dysfunction localised to specific brain regions (topological) and dysfunction related to connections between brain regions (hodological), combining evidence from tractography, functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) studies. Patients prone to hallucinations have complex, task-specific hodological abnormalities that persist between hallucination episodes. During hallucinations, topological increases in activity are found whose location defines hallucination content and modality. Whether these activity increases are accompanied by transient hodological change is unclear. The second part of the paper addresses this issue in EEG and fMRI studies of a 200-year-old paradigm. Photic stimulation within a specific frequency and luminance range induces hallucinations of geometrical patterns, colours and motion in normal subjects. By comparing hallucination-inducing with control stimulation, topological activity increases were identified in visual areas whose specialisations matched the induced hallucination contents. During hallucinations, fMRI connectivity between LGN and cortex changed from a positive to negative relationship while EEG connectivity between occipital and other brain regions increased. The complex and dynamic topological and hodological changes during induced hallucinations are consistent with a shift in thalamocortical circuitry from tonic to burst mode and may have direct relevance to the Charles Bonnet Syndrome. The third part of the paper considers the relevance of the finding to other disorders, examines the strengths and limitations of our current imaging approaches to connectivity and looks to future developments in the field.