Psychosis and autism: magnetic resonance imaging study of brain anatomy.

BACKGROUND: Autism-spectrum disorder is increasingly recognised, with recent studies estimating that 1% of children in South London are affected. However, the biology of comorbid mental health problems in people with autism-spectrum disorder is poorly understood. AIMS: To investigate the brain anatomy of people with autism-spectrum disorder with and without psychosis. METHOD: We used in vivo magnetic resonance imaging and compared 30 adults with autism-spectrum disorder (14 with a history psychosis) and 16 healthy controls. RESULTS: Compared with controls both autism-spectrum disorder groups had significantly less grey matter bilaterally in the temporal lobes and the cerebellum. In contrast, they had increased grey matter in striatal regions. However, those with psychosis also had a significant reduction in grey matter content of frontal and occipital regions. Contrary to our expectation, within autism-spectrum disorder, comparisons revealed that psychosis was associated with a reduction in grey matter of the right insular cortex and bilaterally in the cerebellum extending into the fusiform gyrus and the lingual gyrus. CONCLUSIONS: The presence of neurodevelopmental abnormalities normally associated with autism-spectrum disorder might represent an alternative 'entry-point' into a final common pathway of psychosis.

Event-related potential correlates of paranormal ideation and unusual experiences.

Separate dimensions of schizotypy have been differentially associated with electrophysiological measures of brain function, and further shown to be modified by sex/gender. We investigated event-related potential (ERP) correlates of two subdimensions of positive schizotypy, paranormal ideation (PI) and unusual experiences (UEs). Seventy-two individuals with no psychiatric diagnosis (men=36) completed self-report measures of UE and PI and performed an auditory oddball task. Average scores for N100, N200 and P300 amplitudes were calculated for left and right anterior, central and posterior electrode sites. Multiple linear regression was used to examine the relationships between the measures of schizotypy and ERPs across the entire sample, as well as separately according to sex. PI was inversely associated with P300 amplitude at left-central sites across the entire sample, and at right-anterior electrodes in women only. Right-anterior P300 and right-posterior N100 amplitudes were negatively associated with UE in women only. Across the entire sample, UE was negatively associated with left-central N100 amplitude, and positively associated with left-anterior N200 amplitude. These results provide support from electrophysiological measures for the fractionation of the positive dimension of schizotypy into subdimensions of PI and UE, and lend indirect support to dimensional or quasidimensional conceptions of psychosis. More specifically, they suggest that PI may be associated with alteration in contextual updating processes, and that UE may reflect altered sensory/early-attention (N100) mechanisms. The sex differences observed are consistent with those previously observed in individuals with schizophrenia.

Modulation of neural response to happy and sad faces by acute tryptophan depletion.

BACKGROUND: Central serotonin (5HT) plays a major role in emotional processing. We used functional neuroimaging (fMRI) to investigate the effects of experimental manipulation of central 5HT levels on the regional neural response to happy and sad facial expressions. METHODS: Ten healthy participants (eight men and two women) were scanned during an implicit emotional processing task after receiving a tryptophan-free (acute tryptophan depletion, ATD) or a balanced amino acid drink in a double-blind design. RESULTS: ATD lowered total plasma tryptophan concentration by 80%. There was no significant effect on subjective mood ratings, on response accuracy and on reaction times. Compared to sham depletion, ATD attenuated activation in the right medial/inferior frontal gyrus, the posterior cingulate cortex, the occipital and parietal cortex bilaterally, the right hippocampus, claustrum and insula. Conversely, ATD was associated with relatively increased activation in the left inferior frontal gyrus. ATD had differential effects on activation during the processing of happy and sad faces in the right putamen and in the left superior temporal gyrus. CONCLUSIONS: In both cortical and sub-cortical regions, the neural response associated with processing emotional faces is significantly modulated by 5HT manipulation resulting from ATD. Moreover, in certain areas, this effect of 5HT depends on the emotional valence of the stimulus.

Effect of acute tryptophan depletion on pre-frontal engagement.

BACKGROUND: Serotonin is known to modulate cognitive functioning and has been implicated in the cognitive deficits associated with affective disorders. The present study examined regional brain activation during two tasks that are known to engage the pre-frontal cortex and are performed poorly by patients with depression and bipolar disorder. We tested the hypothesis that acute tryptophan depletion (ATD) would attenuate pre-frontal activation during both tasks. MATERIALS AND METHODS: Ten healthy right-handed volunteers were studied using functional MRI whilst performing a 2-back verbal working memory task and a phonological verbal fluency task. Subjects were studied in two separate sessions, after either a tryptophan-free or a balanced amino acid drink, in a double-blind design. Task performance and mood were measured online. RESULTS: Relative to sham depletion, ATD attenuated activation in the right superior frontal gyrus during the 2-back task and in the medial frontal gyrus and precuneus during the verbal fluency task. ATD lowered total plasma tryptophan by 79% but had no significant effect on either task performance or mood. CONCLUSIONS: The engagement of pre-frontal cortex during verbal working memory and verbal fluency tasks is significantly modulated by central serotonergic activity. The different location of these modulatory effects within the frontal cortex may reflect the engagement of distinct cognitive processes by the respective tasks.

Event-related potential correlates of depression, insight and negative symptoms in males with recent-onset psychosis.

OBJECTIVE: The neurobiology of clinical characteristics -in particular depression, insight and negative symptoms- in recent-onset psychosis (ROP) was studied using event-related potentials (ERPs). METHODS: Twenty right-handed ROP men and 20 controls completed an auditory-oddball task. ROP men had minimum exposure to antipsychotic medication. N100, N200 and P300 were studied to ascertain the effects of (a) diagnosis (patients versus controls), and (b) clinical characteristics. RESULTS: ROP men had significantly lower anterior N100, enhanced N200 at T3, and lower P300 at Pz than controls. Lower right-anterior N100 and enhanced right-anterior N200 amplitude explained 47.7% of negative symptoms. Left-central N100 amplitude explained 30.28% of negative symptoms. Lower left-posterior and higher right-posterior P300 amplitude explained 65.99% of total symptoms. Lower left-central N100, enhanced left-central N200 and depression explained 78.8% of impairments in insight and judgement. Impaired insight/judgement correlated positively with right-anterior N200 and was identified as the most significant co-efficient for depression. CONCLUSIONS: Disturbed selective-attention and executive function indexed by N100 and N200, respectively, are associated with poor insight and negative symptoms. A complex interaction exists between insight and depression. SIGNIFICANCE: The current results demonstrate a biological basis of insight and depression and a complex interaction between the two, perhaps mediated by executive function, in early psychosis.

The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial.

RATIONALE: Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main cannabinoid ∆-9-tetrahydrocannabinol (THC). ∆-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC. OBJECTIVES: To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers. METHODS: Ten male cannabis users (<25 use occasions) were recruited for this within-subjects, placebo-controlled, double-blind, cross-over pilot study. 10mg oral pure THCV or placebo were administered daily for five days, followed by 1mg intravenous THC on the fifth day. RESULTS: THCV was well tolerated and subjectively indistinguishable from placebo. THC did not significantly increase psychotic symptoms, paranoia or impair short-term memory, while still producing significant intoxicating effects. Delayed verbal recall was impaired by THC and only occurred under placebo condition (Z=-2.201, p=0.028), suggesting a protective effect of THCV. THCV also inhibited THC-induced increased heart rate (Z=-2.193, p=0.028). Nine out of ten participants reported THC under THCV condition (compared to placebo) to be subjectively weaker or less intense (χ(2)=6.4, p=0.011). THCV in combination with THC significantly increased memory intrusions (Z=-2.155, p=0.031). CONCLUSION: In this first study of THC and THCV, THCV inhibited some of the well-known effects of THC, while potentiating others. These findings need to be interpreted with caution due to a small sample size and lack of THC-induced psychotomimetic and memory-impairing effect, probably owing to the choice of dose.

Tryptophan depletion reduces right inferior prefrontal activation during response inhibition in fast, event-related fMRI.

RATIONALE AND OBJECTIVE: In animal and human studies, the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) has been implicated in mediating impulsiveness and aggression. To test the hypothesis that 5-HT modulates neuro-cognitive brain activation during inhibitory control, we examined the effect of acute tryptophan depletion (ATD), a dietary challenge, which has been shown to decrease 5-HT synthesis in the brain, on functional brain activation during a go/no-go task. METHODS: Nine healthy, right-handed volunteers performed a rapid, event-related go/no-go task in two functional magnetic resonance imaging (fMRI) scanning sessions, 5 h after either a tryptophan-free or a balanced amino acid drink in a double-blind, sham depletion-controlled, counterbalanced, crossover design. The task required subjects to selectively execute or inhibit a motor response. Tryptophan depletion significantly lowered total plasma tryptophan concentration by 80%, but did not significantly alter inhibitory performance or mood ratings. RESULTS: ATD significantly reduced right orbito-inferior prefrontal activation during the no-go condition, and increased activation in superior and medial temporal cortices. CONCLUSIONS: These findings provide neuro-functional evidence of a serotonergic modulation of right inferior prefrontal during inhibitory motor control. The increased engagement of temporal brain regions may reflect compensatory mechanisms.

Full genome screen for Alzheimer disease: stage II analysis.

We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square=7.11, P=0.045, df=1).

Disruption of frontal θ coherence by Δ9-tetrahydrocannabinol is associated with positive psychotic symptoms.

The main ingredient in cannabis, Δ(9)-tetrahydrocannabinol (THC), can elicit acute psychotic reactions in healthy individuals and precipitate relapse in schizophrenic patients. However, the neural mechanism of this is unknown. We tested the hypothesis that THC psychopathology is related to changes in electroencephalography (EEG) power or inter-regional coherence. In a within-subjects design, participants (n=16) were given intravenous THC (1.25 mg) or placebo under double-blind conditions, during EEG recordings. Using fast-Fourier transform, EEG data were analyzed for power and coherence in the delta (1-3.5 Hz), theta (3.5-7 Hz), alpha (8-13 Hz), beta (14-25 Hz), low-gamma (30-40 Hz), and high-gamma (60-70 Hz) bands during engagement in the n-back test of working memory (WM). Compared with placebo, THC evoked positive and negative psychotic symptoms, as measured by the positive and negative syndrome scale (p<0.001) and slowed WM performance (p<0.05). Under THC, theta power was specifically reduced, (p<0.001) regardless of WM load; however, the reduction showed no relationship with psychotic symptoms or WM impairment. Coherence between bi-frontal electrodes in the theta band was also reduced by THC (p<0.05) and these reductions correlated with the change-in positive psychotic symptoms (rho=0.79, p<0.001). Bi-frontal specificity was suggested by the absence of a relationship between psychotic symptoms and fronto-parietal coherence. The results reveal that the pro-psychotic effects of THC might be related to impaired network dynamics with impaired communication between the right and left frontal lobes.

Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.

Delta-9-tetrahydrocannabinol (Delta-9-THC) and Cannabidiol (CBD), the two main ingredients of the Cannabis sativa plant have distinct symptomatic and behavioral effects. We used functional magnetic resonance imaging (fMRI) in healthy volunteers to examine whether Delta-9-THC and CBD had opposite effects on regional brain function. We then assessed whether pretreatment with CBD can prevent the acute psychotic symptoms induced by Delta-9-THC. Fifteen healthy men with minimal earlier exposure to cannabis were scanned while performing a verbal memory task, a response inhibition task, a sensory processing task, and when viewing fearful faces. Subjects were scanned on three occasions, each preceded by oral administration of Delta-9-THC, CBD, or placebo. BOLD responses were measured using fMRI. In a second experiment, six healthy volunteers were administered Delta-9-THC intravenously on two occasions, after placebo or CBD pretreatment to examine whether CBD could block the psychotic symptoms induced by Delta-9-THC. Delta-9-THC and CBD had opposite effects on activation relative to placebo in the striatum during verbal recall, in the hippocampus during the response inhibition task, in the amygdala when subjects viewed fearful faces, in the superior temporal cortex when subjects listened to speech, and in the occipital cortex during visual processing. In the second experiment, pretreatment with CBD prevented the acute induction of psychotic symptoms by Delta-9-tetrahydrocannabinol. Delta-9-THC and CBD can have opposite effects on regional brain function, which may underlie their different symptomatic and behavioral effects, and CBD's ability to block the psychotogenic effects of Delta-9-THC.

Facial emotion processing in criminal psychopathy. Preliminary functional magnetic resonance imaging study.

BACKGROUND: It has been suggested that people with psychopathic disorders lack empathy because they have deficits in processing distress cues (e.g. fearful facial expressions). AIMS: To investigate brain function when individuals with psychopathy and a control group process facial emotion. METHOD: Using event-related functional magnetic resonance imaging we compared six people scoring > or =25 on the Hare Psychopathy Checklist-Revised and nine non-psychopathic healthy volunteers during an implicit emotion processing task using fearful, happy and neutral faces. RESULTS: The psychopathy group showed significantly less activation than the control group in fusiform and extrastriate cortices when processing both facial emotions. However, emotion type affected response pattern. Both groups increased fusiform and extrastriate cortex activation when processing happy faces compared with neutral faces, but this increase was significantly smaller in the psychopathy group. In contrast, when processing fearful faces compared with neutral faces, the control group showed increased activation but the psychopathy group decreased activation in the fusiform gyrus. CONCLUSIONS: People with psychopathy have biological differences from controls when processing facial emotion, and the pattern of response differs according to emotion type.

Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Variation in the urokinase-plasminogen activator gene does not explain the chromosome 10 linkage signal for late onset AD.

Linkage studies indicate that the same region of chromosome 10 contains a risk locus for late onset Alzheimer disease (LOAD) and a QTL for plasma Abeta42 levels suggesting that a single locus may influence risk for AD by elevating plasma Abeta42 [Ertekin-Taner et al., 2000; Myers et al., 2000]. A strong positional and biological candidate is the urokinase-plasminogen activator (PLAU) gene. Eight polymorphisms spanning the entire gene were examined using case control (CC) and family-based association methods. No association was observed by any method making it unlikely that variation in PLAU explains our linkage data.