Search PubMed⌕ Search

Biomedical subjects

James M Stone

Publications and source records attributed to James M Stone.

8 recordsLinked to original sources
PubMed2026

Neurometabolites and Antipsychotic Response in Psychosis: A Mega-Analysis.

IMPORTANCE: Revealing neurobiological markers of antipsychotic nonresponse in psychosis may aid outcome prediction and inform novel treatment targets. OBJECTIVE: To examine differences in neurometabolites in antipsychotic nonresponsive compared to antipsychotic-responsive psychosis using individual participant data and meta-analysis. DATA SOURCES: Web of Science was searched for studies published between January 1, 1980, and November 1, 2025. Authors of 21 eligible studies identified before August 2024 were invited to contribute individual participant data. STUDY SELECTION: Eighteen studies examining neurometabolites by treatment response in psychosis contributed individual participant data for the mega-analysis. These studies plus a further 5 studies were included in the meta-analyses of standardized mean differences and variability. DATA EXTRACTION AND SYNTHESIS: Individual participant data were analyzed using linear mixed models with study as a random effect. Subgroup analyses examined prospective designs and treatment-resistant samples. Published group means and standard deviations were extracted for meta-analyses. MAIN OUTCOMES AND MEASURES: Group differences in glutamate, glutamate plus glutamine, choline, myo-inositol, N-acetylaspartate, γ-aminobutyric acid, and glutathione in the medial frontal cortex, dorsolateral prefrontal cortex, thalamus, and basal ganglia. RESULTS: The mega-analysis included 1189 participants from 18 studies; of these, 476 were treatment nonresponders (mean [SD] age, 33.0 [12.5] years; 340 male), 427 were treatment responders (mean [SD] age, 30.3 [11.5] years; 299 male), and 286 were healthy control individuals (mean [SD] age, 31.0 [12.5] years; 170 male). Compared with the antipsychotic response group, nonresponders showed elevations in medial frontal glutamate (Glass Δ = 0.21; P = .02), glutamate plus glutamine (Glass Δ = 0.29; P = .002), choline (Glass Δ = 0.22; P = .03), and myo-inositol (Glass Δ = 0.35; P = .001); similar elevations were observed relative to control individuals. Elevated medial frontal glutamate plus glutamine in antipsychotic nonresponders compared with responders was also observed prospectively in first-episode psychosis (Glass Δ = 0.41; P = .002), whereas myo-inositol elevations were greatest in individuals meeting criteria for treatment-resistance (Glass Δ = 0.64; P = .001). The meta-analysis of 23 studies (1844 participants) also showed elevated medial frontal choline and myo-inositol in antipsychotic nonresponse compared with response. CONCLUSIONS AND RELEVANCE: These findings provide evidence of an association between antipsychotic nonresponse in psychosis with elevations in medial frontal glutamate, choline, and myo-inositol. The presence of elevations in these markers supports the continued investigation of glutamate-acting and inflammatory pathway-associated interventions for psychosis and schizophrenia.

Humans↗
PubMed2007

Internet-enabled high-resolution brain mapping and virtual microscopy.

Virtual microscopy involves the conversion of histological sections mounted on glass microscope slides to high-resolution digital images. Virtual microscopy offers several advantages over traditional microscopy, including remote viewing and data sharing, annotation, and various forms of data mining. We describe a method utilizing virtual microscopy for generation of internet-enabled, high-resolution brain maps and atlases. Virtual microscopy-based digital brain atlases have resolutions approaching 100,000 dpi, which exceeds by three or more orders of magnitude resolutions obtainable in conventional print atlases, MRI, and flat-bed scanning. Virtual microscopy-based digital brain atlases are superior to conventional print atlases in five respects: (1) resolution, (2) annotation, (3) interaction, (4) data integration, and (5) data mining. Implementation of virtual microscopy-based digital brain atlases is located at BrainMaps.org, which is based on more than 10 million megapixels (35 terabytes) of scanned images of serial sections of primate and non-primate brains with a resolution of 0.46 microm/pixel (55,000 dpi). The method can be replicated by labs seeking to increase accessibility and sharing of neuroanatomical data. Online tools offer the possibility of visualizing and exploring completely digitized sections of brains at a sub-neuronal level and can facilitate large-scale connectional tracing, histochemical, and stereological analyses.

Animals↗
PubMed2006

[123I]TPCNE--a novel SPET tracer for the sigma-1 receptor: first human studies and in vivo haloperidol challenge.

[123I]TPCNE (1(trans-[123I]iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl] piperidine; Ki = 0.67 nM; log P = 3.36) is a novel sigma-1 receptor SPET ligand. In this study, we developed an optimized labeling method for [123I]TPCNE and investigated the kinetics, binding characteristics, and whole-body distribution of this tracer for the first time in humans. We also performed a challenge with the sigma-1 receptor antagonist haloperidol against [123I]TPCNE. Seven healthy volunteers were recruited. Dynamic brain SPET scans were performed following i.v. administration of 185 MBq [123I]TPCNE in all seven subjects. Three of the subjects were given oral haloperidol (2.5 mg) approximately 1 h before the scan. The dynamic data were analyzed with both reversible and irreversible compartmental models.[123I]TPCNE showed high uptake in brain and liver. All non-haloperidol-treated subjects showed a high whole-brain uptake (average: 8.7% of injected activity). No significant clearance of the tracer was seen up to 30 h post injection. In the haloperidol-treated subjects, the time-activity curves clearly demonstrated clearance of the tracer from the brain. Regional radioactivity concentrations were reduced by haloperidol from 42% in the cerebellum to 73% in the thalamus.[(123)I]TPCNE demonstrated high brain uptake, with highest binding found in the posterior cingulate. A region in which binding was unaffected by haloperidol pretreatment could not be identified, and the time-activity data were best described by an irreversible model.

Adult↗
PubMed2006

Ketamine displaces the novel NMDA receptor SPET probe [(123)I]CNS-1261 in humans in vivo.

[(123)I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intra-channel PCP/ketamine/MK-801 site of the N-methyl-d-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intra-channel PCP/ketamine/MK-801 site) on [(123)I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [(123)I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [(123)I]CNS-1261 V(T) in most of the brain regions examined (P<.05). [(123)I]CNS-1261 appears to be a specific ligand in vivo for the intra-channel PCP/ketamine/MK-801 NMDA binding site.

Adult↗
PubMed2006

Antipsychotic drug action: targets for drug discovery with neurochemical imaging.

Schizophrenia is a serious lifelong mental illness for which current treatments may only be partially effective. All antipsychotic medications available at present are thought to exert their main antipsychotic effect through antagonism of dopamine D2 receptors. Clozapine is the most effective antipsychotic drug currently available, but it can cause serious side effects, including agranulocytosis and diabetes. Pharmacologic factors that distinguish clozapine from other antipsychotic drugs have been studied to try to develop safer drugs with similar efficacy to clozapine. These have met with limited success. Neurochemical imaging techniques, such as positron emission tomography, single photon emission tomography and magnetic resonance spectroscopy, have been used to study antipsychotic drug action in living human subjects. These techniques shed a great deal of light on the mechanisms of antipsychotic action and have revealed a number of novel targets for future drug development in schizophrenia. Next-generation antipsychotic medications will aim to improve on the efficacy and tolerability of currently available medications. The authors believe that they are likely to achieve this through drug action at non-D2 sites. Future research and drug development, including the development of medications to prevent progression from the prepsychotic stage to schizophrenia, will rely heavily on neurochemical imaging methods at all stages in the drug-discovery pipeline.

Animals↗
PubMed2005

Non-uniform blockade of intrastriatal D2/D3 receptors by risperidone and amisulpride.

RATIONALE: Atypical antipsychotic drugs have been shown to preferentially affect extrastriatal (mesolimbic) D2/D3 receptors over those within the striatum (nigrostriatal). The striatum does not contain exclusively nigrostriatal dopamine tracts, however. The caudate nucleus and ventral parts of the striatum primarily contain limbic and associative dopamine pathways more relevant to psychosis. OBJECTIVES: We tested the hypothesis that two pharmacologically distinct atypical antipsychotic drugs, amisulpride and risperidone, would preferentially occupy of D2/D3 dopamine receptors in limbic and associative regions of the striatum. METHODS: Eight amisulpride-treated patients, six risperidone-treated patients and six age- and sex-matched healthy controls were recruited. Dynamic SPET studies were performed after bolus injection of [123I]epidepride. Binding potential (BP) images were generated using a modified Logan method and aligned between subjects. Regions of interest (ROIs) were placed around head of caudate and putamen bilaterally on an average BP map derived from aligned control images. These ROIs were then applied user-independently to the BP maps for each subject to calculate BP for head of caudate and putamen. Mean occupancy of D2/D3 receptors in each ROI was determined by reference to the drug-free healthy volunteer group. Occupancy values for head of caudate and putamen were compared using paired Student's t test. RESULTS: D2/D3 receptor occupancy was 42% in caudate and 31% in putamen for risperidone (t=5.9, df=11, p=0.0001) and 51% in caudate and 37% in putamen for amisulpride (t=11.1, df=15, p<0.0001). CONCLUSIONS: Amisulpride and risperidone both show selective occupancy for limbic and associative D2/D3 receptors within the striatum.

Adult↗
PubMed2005

Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo.

BACKGROUND: Antipsychotic drugs modulate N-methyl-D-aspartate (NMDA) receptor function in animals. The novel single photon emission tomography (SPET) radiotracer [123I]CNS-1261 binds to the PCP/MK-801 intrachannel site of the NMDA receptor, allowing the noninvasive estimation of NMDA receptor activity in living humans. We used [123I]CNS-1261 to determine whether binding to the NMDA receptor intrachannel PCP/MK-801 site is affected by schizophrenia or by treatment with typical antipsychotics and clozapine in vivo. METHODS: Three groups of schizophrenia patients were recruited-drug free (n = 5), typical antipsychotic treated (n = 7), and clozapine treated (n = 9)-as well as a control group of healthy normal volunteers (n = 13). All underwent [123I]CNS-1261 SPET scanning. Total volume of distribution of [123I]CNS-1261 was determined within predefined user-independent regions of interest after alignment of all images to a common template. RESULTS: There was no apparent difference in total volume of distribution of [123I]CNS-1261 in drug-free patients relative to healthy control subjects. A nonsignificant reduction in total volume of distribution was observed in typical antipsychotic treated patients. A significant decline in total volume of distribution of [123I]CNS-1261 was observed in all examined brain regions in the clozapine-treated patient group relative to healthy control subjects (p < .005). CONCLUSIONS: Clozapine treatment resulted in a global reduction in [123I]CNS-1261 binding to the NMDA receptor intrachannel PCP/MK-801 site in vivo. This supports an effect of the drug on glutamatergic systems that could be exploited for future antipsychotic drug discovery.

Adult↗