ACUTE EFFECTS OF DIAZEPAM ON HIPPOCAMPAL RESTING CEREBRAL BLOOD FLOW IN INDIVIDUALS AT CLINICAL HIGH-RISK FOR PSYCHOSIS
Bibliographic record
Abstract
Abstract Background Psychosis-relevant preclinical studies have demonstrated GABAergic drugs such as benzodiazepines can downregulate hippocampal hyperactivity and prevent the emergence of psychosis- like phenotypes. However, whether benzodiazepines can reduce and normalise increased hippocampal resting cerebral blood flow (rCBF) observed in individuals at clinical high-risk for psychosis (CHR-P) remains unknown. Aims To determine whether an acute dose of diazepam can reduce and normalise hippocampal and subfield rCBF in CHR-P individuals. Methods We conducted a within-subject, double-blind, placebo-controlled, randomised, cross-over design study in 24 CHR-P individuals (mean [± SD] age: 24.1 [±4.8] years, 15F). Participants underwent two MRI sessions, three weeks apart; once under a single dose of diazepam (5 mg) and once under placebo (50 mg ascorbic acid). A previously collected dataset of 21 healthy controls (HC) was used for comparison. rCBF was measured using pseudocontinuous arterial spin labelling and sampled in each participant’ s native space using participant-specific hippocampus/subfield masks generated with the MAGeT Brain toolbox. Individual Mixed ANCOVAs (covarying for global rCBF, age, and sex) and linear mixed-effects models (participant ID as random effect) investigated the effect of group (CHR-P placebo vs. HC and CHR-P diazepam vs. HC) and drug (CHR-P placebo vs. diazepam), respectively, on hippocampal/subfield rCBF per ROI. These models were repeated voxel-wise in study-specific template space to investigate whole-brain effects. Significance was set at pFDR<0.05. Pearson’ s correlations assessed whether baseline clinical characteristics could predict diazepam-induced changes in hippocampal rCBF. Results CHR-P individuals under placebo showed significantly increased rCBF compared to HC in the hippocampus (F(1,41)=24.7, pFDR<0.001), and this was significantly reduced by diazepam (t(69)=-5.1, pFDR <0.001) to the extent that it no longer differed from HC (F(1,41)=0.4, pFDR=0.204). This effect of hyperactivity and normalisation under diazepam was seen across all subfields studied and in several psychosis-relevant cortical and subcortical regions connected to the hippocampus, including medial/dorsolateral prefrontal cortex, nucleus accumbens, and amygdala. Smallest reductions in diazepam-induced bilateral hippocampal rCBF change were observed in CHR-P individuals with highest attenuated psychotic symptom severity (r= 0.494, p=0.014) and poorest social functioning (r=-0.416, p=0.043) at baseline, which appeared to be driven by the left CA4/DG (positive symptom severity: r=0.528, p=0.008; social functioning: r=-0.503, p=0.012). Conclusions Acute diazepam challenge effectively reduced increased rCBF in the hippocampus and subfields of CHR-P individuals, providing proof-of-concept of the efficacy of GABA-enhancing drugs to modulate hippocampal hyperactivity in this clinical group. Our results that CHR-P individuals who were clinically most unwell showed the smallest changes in rCBF suggest the development of more hippocampal-selective GABAergic pharmacological agents (e.g., those targeting a5-GABAA receptors) as a promising strategy for regulating hippocampal hyperactivity and preventing psychosis development.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".