Bi-directional and multi-modal effects of dexamphetamine on spatial binding windows in healthy individuals.

OBJECTIVES: Stimuli that are separated by a short window of space or time, known as spatial and temporal binding windows (SBW/TBWs), may be perceived as separate. Widened TBWs are evidenced in schizophrenia, although it is unclear if the SBW is similarly affected. The current study aimed to assess if dexamphetamine (DEX) may increase SBWs in a multimodal visuo-tactile illusion, potentially validating usefulness as an experimental model for multimodal visuo-tactile hallucinations in schizophrenia, and to examine a possible association between altered binding windows (BWs) and working memory (WM) suggested by previous research. METHODS: A placebo-controlled, double-blinded, and counter-balanced crossover design was employed. Permuted block randomisation was used for drug order. Healthy participants received DEX (0.45 mg/kg, PO, b.i.d.) or placebo (glucose powder) in capsules. The Rubber Hand Illusion (RHI) and Wechsler Adult Intelligence Scale Spatial Span was employed to determine whether DEX would alter SBWs and WM, respectively. Schizotypy was assessed with a variety of psychological scales. RESULTS: Most participants did not experience the RHI even under normal circumstances. Bi-directional and multimodal effects of DEX on individual SBWs and schizotypy were observed, but not on WM. CONCLUSIONS: Bidirectional multimodal effects of DEX on the RHI and SBWs were observed in individuals, although not associated with alterations in WM.

Dexamphetamine increased speech and visual unimodal illusions in healthy participants without affecting temporal binding window.

OBJECTIVE: Stimuli received beyond a very short timeframe, known as temporal binding windows (TBWs), are perceived as separate events. In previous audio-visual multisensory integration (McGurk effect) studies, widening of TBWs has been observed in people with schizophrenia. The present study aimed to determine if dexamphetamine could increase TBWs in unimodal auditory and unimodal visual illusions that may have some validity as experimental models for auditory and visual hallucinations in psychotic disorders. METHODS: A double-blind, placebo-controlled, counter-balanced crossover design with permuted block randomisation for drug order was followed. Dexamphetamine (0.45 mg/kg, PO, q.d.) was administered to healthy participants. Phantom word illusion (speech illusion) and visual-induced flash illusion/VIFI (visual illusion) tests were measured to determine if TBWs were altered as a function of delay between stimuli presentations. Word emotional content for phantom word illusions was also analysed. RESULTS: Dexamphetamine significantly increased the total number of phantom words/speech illusions (p < 0.01) for pooled 220-1100 ms ISIs in kernel density estimation and the number of positive valence words heard (beta = 2.20, 95% CI [1.86, 2.55], t = 12.46, p < 0.001) with a large effect size (std. beta = 1.05, 95% CI [0.89, 1.22]) relative to placebo without affecting the TBWs. For the VIFI test, kernel density estimation for pooled 0-801 ms ISIs showed a significant difference (p < 0.01) in the data distributions of number of target flash (es) perceived by participants after receiving dexamphetamine as compared with placebo. CONCLUSIONS: Overall, healthy participants who were administered dexamphetamine (0.45 mg/kg, PO, q.d.) experienced increases in auditory and visual illusions in both phantom word illusion and VIFI tests without affecting their TBWs.

The effects of caffeine and d-amphetamine on spatial span task in healthy participants.

Studies that examined the effect of amphetamine or caffeine on spatial working memory (SWM) and verbal working memory (VWM) have used various tasks. However, there are no studies that have used spatial span tasks (SSTs) to assess the SWM effect of amphetamine and caffeine, although some studies have used digit span tasks (DST) to assess VWM. Previous reports also showed that increasing dopamine increases psychosis-like experiences (PLE, or schizotypy) scores which are in turn negatively associated with WM performance in people with high schizotypy and people with schizophrenia. Therefore, the present study aimed to examine the influence of d-amphetamine (0.45 mg/kg, PO), a dopamine releasing stimulant, on SST, DST, and on PLE in healthy volunteers. In a separate study, we examined the effect of caffeine, a nonspecific adenosine receptor antagonist with stimulant properties, on similar tasks. METHODS: Healthy participants (N = 40) took part in two randomized, double-blind, counter-balanced placebo-controlled cross-over pilot studies: The first group (N = 20) with d-amphetamine (0.45 mg/kg, PO) and the second group (N = 20) with caffeine (200 mg, PO). Spatial span and digit span were examined under four delay conditions (0, 2, 4, 8 s). PLE were assessed using several scales measuring various aspects of psychosis and schizotypy. RESULTS: We failed to find an effect of d-amphetamine or caffeine on SWM or VWM, relative to placebo. However, d-amphetamine increased a composite score of psychosis-like experiences (p = 0.0005), specifically: Scores on Brief Psychiatric Rating Scale, Perceptual Aberrations Scale, and Magical Ideation Scale were increased following d-amphetamine. The degree of change in PLE following d-amphetamine negatively and significantly correlated with changes in SWM, mainly at the longest delay condition of 8 s (r = -0.58, p = 0.006). CONCLUSION: The present results showed that moderate-high dose of d-amphetamine and moderate dose of caffeine do not directly affect performances on DST or SST. However, the results indicate that d-amphetamine indirectly influences SWM, through its effect on psychosis-like experiences. CLINICAL TRIAL REGISTRATION NUMBER: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry) for caffeine study, and ACTRN12608000610336 for d-amphetamine study.

Nabilone Impairs Spatial and Verbal Working Memory in Healthy Volunteers.

Background: Memory impairments and psychosis-like experiences can be adverse effects of cannabis use. However, reports on the cognitive impact of cannabis use are not consistent. There are also limited studies on the psychotomimetic effects of cannabinoid compounds to reveal the association between cannabis and psychosis. Therefore, we investigated the effect of acute cannabinoid intoxication on verbal working memory (VWM) and spatial working memory (SWM) following oral doses of the synthetic cannabinoid agonist, nabilone (1-2 mg, oral). We further investigated the effect of nabilone on psychosis-like experiences (schizotypy scores) and associations of schizotypy with VWM and SWM. Methods: Healthy participants (n=28) completed spatial and digit span tasks across different delay conditions (0, 6, 12, and 18 sec) after receiving nabilone (1-2 mg, PO) or placebo in a randomized, double-blind, counterbalanced, crossover manner. A subset of participants completed a short battery of schizotypy measures (n=25). Results: Nabilone impaired VWM (p=0.03, weak effect size η2=0.02) and SWM (p=0.00016, η2=0.08). Nabilone did not significantly change overall schizotypy scores. Schizotypy scores were negatively correlated with working memory (WM) averaged across all delays and both modalities, under placebo (ρ=-0.41, p=0.04). In addition, there were significant negative correlations between occasions of cannabis use and overall WM averaged scores across drug treatments (ρ=-0.49, p=0.007) and under placebo (ρ=-0.45, p=0.004). The results showed that the drug effect in the less frequent cannabis users was more pronounced on the SWM (p<0.01) and VWM (p<0.01), whereas there appeared to be little drug effect in the frequent cannabis users. Conclusion: Low doses of synthetic cannabinoid impaired SWM and VWM, indicating that exogenous activation of the cannabinoid system influences cognitive performance. Further, the results replicated previous findings that schizotypy is correlated with deficits in WM. Clinical Trial Registry Name: Nabilone and caffeine effects on the perceptions of visually, auditory, tactile and multimodal illusions in healthy volunteers. Clinical Trial Registration Number: CT-2018-CTN-02561 (Therapeutic Goods Administration Clinical Trial Registry) and ACTRN12618001292268 (The Australian New Zealand Clinical Trials Registry).

Higher Serum C-Reactive Protein Levels in Catatonic Patients: A Comparison to Non-catatonic Patients and Healthy Controls.

Catatonia is a psychomotor syndrome defined by a constellation of predominantly motor symptoms. The aim of the present study was to determine whether recently admitted psychiatric patients with catatonia exhibited higher serum C-reactive protein (hs-CRP) levels compared to non-catatonic psychiatric patients and healthy controls (HCs). Recently admitted psychiatric patients were screened and evaluated for the catatonia syndrome using the Bush-Francis Catatonia Rating Scale and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). The study sample was formed by 150 individuals (39 male and 111 female), including 51 catatonic patients, 55 non-catatonic patients, and 44 HCs. Serum hs-CRP levels were processed with the enzyme-linked immunosorbent assay. Serum levels of creatine kinase (CK), adrenocorticotropic hormone (ACTH), immunoglobulin G (IgG), complement component 3 (C3), and complement component 4 (C4) were also determined. There was a significantly higher percentage of patients with high inflammatory levels (hs-CRP > 3000ng/ml) in the catatonic (43.1%) than in the non-catatonic (14.5%) or HCs group (9.1%) (χ 2 =18.9, P < .001). Logistic regression showed that catatonic patients had significantly higher hs-CRP levels compared to non-catatonic patients even after controlling for other clinical and laboratory variables (OR = 3.52, P = .015, 95% CI 1.28-9.79). Multiple linear regression analysis revealed that log-transformed hs-CRP was independently predicted by body mass index and log-transformed C4, ACTH, and Cortisol in catatonic patients. Findings of the present study suggest that catatonia is specifically linked to a higher level of systemic inflammation, not merely attributable to the overall psychopathology, or alterations in the stress level and complement system.

Dexamphetamine effects on prepulse inhibition (PPI) and startle in healthy volunteers.

RATIONALE: Amphetamine challenge in rodent prepulse inhibition (PPI) studies has been used to model potential dopamine involvement in effects that may be relevant to schizophrenia, though similar studies in healthy humans have failed to report replicable or robust effects. OBJECTIVES: The present study investigated dexamphetamine effects on PPI in healthy humans with an increased dose and a range of startling stimulus intensities to determine participants' sensitivity and range of responses to the stimuli. METHODS: A randomised, placebo-controlled dexamphetamine (0.45 mg/kg, per os.), double-blind, counterbalanced, within-subject design was used. PPI was measured in 64 participants across a range of startling stimulus intensities, during two attention set conditions (ATTEND and IGNORE). Startle magnitudes for pulse-alone and prepulse-pulse magnitudes were modelled using the startle reflex magnitude (sigmoid) function. Parameters were extracted from these fits, including the upper limit of the asymptote (maximum startle reflex capacity, R MAX), intensity threshold, stimulus intensity that elicits a half-maximal response (ES50) and the maximum rate of change of startle response magnitude to an increase in stimulus intensity. RESULTS: Dexamphetamine increased the threshold and ES50 of the response to pulse-alone trials in both sexes and reduced R MAX exclusively in females. Dexamphetamine modestly increased PPI of the R MAX across both attention conditions. PPI of R MAX was reduced during the ATTEND condition compared to the IGNORE condition. CONCLUSIONS: Results indicate that sex differences exist in motor, but not sensory, components of the startle reflex. Findings also reveal that administration of 0.45 mg/kg dexamphetamine to healthy humans does not mimic PPI effects observed in schizophrenia.

Evaluation of radiosurgery techniques--cone-based linac radiosurgery vs tomotherapy-based radiosurgery.

Performances of radiosurgery of intracranial lesions between cone-based Linac system and Tomotherapy-based system were compared in terms of dosimetry and time. Twelve patients with single intracranial lesion treated with cone-based Linac radiosurgery system from 2005 to 2009 were replanned for Tomotherapy-based radiosurgery treatment. The conformity index, homogeneity index (HI), and gradient score index (GSI) of each case was calculated. The Wilcoxon matched-pair test was used to compare the 3 indices between both systems. The cases with regular target (n = 6) and those with irregular target (n = 6) were further analyzed separately. The estimated treatment time between both systems was also compared. Significant differences were found in HI (p = 0.05) and in GSI (p = 0.03) for the whole group. Cone-based radiosurgery was better in GSI whereas Tomotherapy-based radiosurgery was better in HI. Cone-based radiosurgery was better in conformity index (p = 0.03) and GSI (p = 0.03) for regular targets, whereas Tomotherapy-based radiosurgery system performed significantly better in HI (p = 0.03) for irregular targets. The estimated total treatment time for Tomotherapy-based radiosurgery ranged from 24 minutes to 35 minutes, including 15 minutes of pretreatment megavoltage computed tomography (MVCT) and image registration, whereas that for cone-based radiosurgery ranged from 15 minutes for 1 isocenter to 75 minutes for 5 isocenters. As a rule of thumb, Tomotherapy-based radiosurgery system should be the first-line treatment for irregular lesions because of better dose homogeneity and shorter treatment time. Cone-based Linac radiosurgery system should be the treatment of choice for regular targets because of the better dose conformity, rapid dose fall-off, and reasonable treatment time.

The use of background EEG activity to determine stimulus timing as a means of improving rTMS efficacy in the treatment of depression: a controlled comparison with standard techniques.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) treatment of depression utilizes numerous predetermined patterns of stimulation. As an alternative to using invariant stimulus timing parameters, the interactive technique delivers individual stimuli based on the background electroencephalogram (EEG) activity. OBJECTIVE: This study examines the use of an EEG-dependent technique as a means to enhance the efficacy of rTMS in the treatment of depression. METHODS: Forty-four patients with treatment-refractory major depression were treated, in a randomized, doubleblind, 4-week trial, with two different rTMS stimulus timing techniques (left dorsolateral prefrontal cortex). Standard rTMS utilized 10-Hz stimuli, whereas interactive rTMS applied individual stimuli in response to a selected pattern of background EEG activity analyzed in real time. Hamilton Depression Rating Scale (HDRS) and the Beck's Depression Inventory-II (BDI) scores were recorded at baseline, 2 weeks and after the final treatment. RESULTS: The interactive group showed a trend toward greater efficacy than the standard group in both absolute (t=-1.68; P=.100) and percentage (t=-1.74; P=.090) change in scores on HDRS (and similarly BDI). The response rate (>50% reduction) for the interactive technique of 43% (9/21) was also different to that of the standard technique (22%; 5/23; odds ratio: 2.70). CONCLUSIONS: The use of EEG-based TMS stimuli has been shown to be feasible in an rTMS clinical trial in treatment-resistant depression. The EEG-based interactive technique was associated with an indication of a trend toward a greater clinical effect than the standard rTMS technique. The interactive technique thus has the potential to refine the rTMS methodology and to enhance efficacy in the treatment of depression.

Neuroleptic-induced catatonia: clinical presentation, response to benzodiazepines, and relationship to neuroleptic malignant syndrome.

Neuroleptic-induced catatonia (NIC), manifested in an extrapyramidal-catatonic syndrome, has been sporadically reported in the literature. Confusion surrounds its relationship to neuroleptic malignant syndrome (NMS) and extrapyramidal reactions to neuroleptics. This study examined (a) its clinical presentation and response to benzodiazepines, (b) the hypothesis that NIC and NMS are on the same spectrum with a continuum of symptom progression, and (c) its possible relationship to extrapyramidal reactions. Of 127 episodes of acute catatonia prospectively identified, 18 were diagnosed with NIC. All catatonia episodes received benzodiazepines. The NIC episodes were analyzed noting their clinical presentations, laboratory findings, and responses to treatments. Their responses to benzodiazepines were compared, with retrospective rating on a 7-point scale, to that for catatonia episodes associated with mania and schizophrenia. The progression of symptoms in each NIC episode was reviewed. The NIC episodes presented predominantly in the stuporous form associated with parkinsonism. Delirium, autonomic abnormality, and elevated serum creatine phosphokinase were all common. Neuroleptic malignant syndrome was diagnosed in 3 episodes (17%). The 3 catatonia groups did not differ significantly in their benzodiazepines responses: 78% (14/18) of NIC, 75% (12/16) of manic catatonia, and 67% (34/51) of schizophrenic catatonia episodes showed full responses. A spectrum of presentation across episodes was noted with simple NIC without delirium, autonomic disturbances, or fever at one end and NMS or malignant NIC at the other end. Symptoms in individual episodes showed a similar continuum progression. No extrapyramidal reactions immediately preceded the NIC episodes. Findings of this study support the hypothesis that NIC and NMS are disorders on the same spectrum and reveal no indication that extrapyramidal reactions progress to NIC.

Diagnosing subtypes of neuroleptic malignant syndrome: an introduction to the Lee-Carroll Scale.

BACKGROUND: Neuroleptic malignant syndrome (NMS) shares common features with catatonia and serotonin syndrome (SS). For instance, catatonia is a risk factor for the development of NMS. METHODS: We performed a pilot study to examine if the Lee-Carroll Scale is able to differentiate the proposed NMS subtypes and explore possible relationship between NMS and SS. A consecutive series of cases reported to the Neuroleptic Malignant Syndrome Information Service (NMSIS) were reviewed with 29 cases of "definite NMS." The Hynes-Vickar Scale (an NMS scale), Hegerl Scale (a SS scale), and Lee-Carroll Scale (an NMS subtype scale) were applied to these case report forms. CONCLUSIONS: Although the groups were too small for statistical analysis, the 2 catatonic NMS subtypes appear to have higher NMS scores on the Hynes-Vickar Scale, and lower SS scores on the Hegerl Scale than the non-catatonic NMS subtype. The scores on the Lee-Carroll Scale were highest for non-catatonic NMS subtype. This pilot study suggests that the Lee-Carroll scale may help differentiate the subtypes of NMS, and provides some support that non-catatonic NMS may be a form of SS. NMS subtypes may be important in the early detection and treatment of NMS.

Catatonic variants, hyperthermic extrapyramidal reactions, and subtypes of neuroleptic malignant syndrome.

BACKGROUND: This case series study examines the hypothesis that neuroleptic malignant syndrome (NMS) is a heterogeneous condition including catatonic variants and non-catatonic pathological reactions to antipsychotics. METHODS: Fourteen episodes of NMS were prospectively identified. Patients were examined for catatonia during the course of NMS. Close monitoring of catatonia episodes and suspected cases of evolving NMS for possible NMS development provided data on the pre-NMS clinical course. All NMS episodes received benzodiazepines. Episodes with catatonia diagnosed were compared with those without catatonia, noting their presentation, clinical course and responses to treatment. RESULTS: Concurrent catatonia was diagnosed in 9 episodes. In 6 of them antecedent catatonia progressed to NMS following antipsychotic exposure (NMS of antipsychotic-converted catatonia). In 3 episodes, a parkinsonian-catatonic syndrome with fever and autonomic abnormality developed in reaction to antipsychotics (NMS of antipsychotic-induced catatonia). Catatonia was not diagnosed in 5 during the longitudinal course of NMS. A severe extrapyramidal reaction to antipsychotics with associated delirium preceded all 5 episodes. Seven of the 9 NMS episodes with catatonia and none of the 5 without catatonia showed significant responses to benzodiazepines. CONCLUSIONS: The preliminary findings support the hypothesis that NMS is a heterogeneous condition including catatonic variants and non-catatonic hyperthermic extrapyramidal reactions to antipsychotics, differing in presentation, clinical course, and treatment responses.

Chronic 'speech catatonia' with constant logorrhea, verbigeration and echolalia successfully treated with lorazepam: a case report.

Logorrhea, verbigeration and echolalia persisted unremittingly for 3 years, with occasional short periods of motoric excitement, in a patient with mild intellectual handicap suffering from chronic schizophrenia. The speech catatonic symptoms, previously refractory to various antipsychotics, responded promptly to lorazepam, a benzodiazepine with documented efficacy in the treatment of acute catatonia but not chronic catatonia. It is suggested that pathways in speech production were selectively involved in the genesis of the chronic speech catatonic syndrome, possibly a rare form of chronic catatonia not previously described.

Clozapine withdrawal catatonia associated with cholinergic and serotonergic rebound hyperactivity: a case report.

Catatonia as a clozapine withdrawal syndrome has not been well documented. There is only 1 case of excited catatonia described with the diagnosis made according to strict criteria. The authors report a patient who developed a catatonic stuporous state following abrupt discontinuation of clozapine, associated with features of cholinergic and serotonergic hyperactivity. The catatonic state resolved within 1 week with reinstatement of clozapine. It is suggested that serotonergic hyperactivity was involved, contributed by cholinergic rebound, in the pathogenesis of this patient's clozapine withdrawal catatonic syndrome.