Biomedical subjects

Allan R Sampson

Publications and source records attributed to Allan R Sampson.

18 recordsLinked to original sources

PubMed2007

Primary visual cortex volume and total neuron number are reduced in schizophrenia.

A number of studies that assessed the visual system in subjects with schizophrenia found impairments in early visual processing. Furthermore, functional imaging studies suggested changes in primary visual cortex activity in subjects with schizophrenia. Interestingly, postmortem studies of subjects with schizophrenia reported an increased density of neurons in the primary visual cortex (Brodmann's area 17, BA17). The observed changes in visual processing may thus be reflected in structural changes in the circuitry of BA17. To characterize the structural changes further we used stereological methods based on unbiased principles of sampling (Cavalieri's principle and the optical fractionator) to estimate the total volume and neuron number of BA17 in postmortem brains from 10 subjects with schizophrenia and 10 matched normal comparison subjects. In addition, we assessed cortical thickness. We found a marked and significant reduction in total neuron number (25%) and volume (22%) of BA17 in the schizophrenia group relative to the normal comparison subjects. In contrast, we found no changes in neuronal density or cortical thickness between the two groups. Subjects with schizophrenia therefore have a smaller cortical area allocated to primary visual perception. This finding suggests the existence of a schizophrenia-related change in cortical parcellation.

Adult↗

PubMed2006

Anatomical evidence of impaired feedforward auditory processing in schizophrenia.

BACKGROUND: Somal volumes of pyramidal cells are reduced within feedforward but not feedback circuits in areas 41 and 42 of the auditory cortex of subjects with schizophrenia. Because neuronal somal volume depends on both the number of axonal terminations onto and furnished by the neuron, we hypothesized that axon terminal densities are reduced in feedforward but not feedback auditory pathways in subjects with schizophrenia. METHODS: We used stereologic methods to quantify the density of a marker of axon terminals, synaptophysin-immunoreactive (SY-IR) puncta, in areas 41 and 42 of 15 subjects with schizophrenia and matched normal comparison subjects. The effect of long-term haloperidol exposure on density of SY-IR puncta was similarly evaluated in nonhuman primates. RESULTS: Synaptophysin-immunoreactive puncta density was 13.6% lower in deep layer 3 of area 41 in the schizophrenia subjects but was not changed in layer 1 of area 41 or in deep layer 3 of area 42. Density of SY-IR puncta did not differ between haloperidol-exposed and control monkeys. CONCLUSIONS: Reduction of SY-IR puncta density is selective for feedforward circuits within primary auditory cortex of subjects with schizophrenia. This deficit may contribute to impairments in auditory sensory processing in this disorder.

Adult↗

PubMed2006

Effect of chronic exposure to antipsychotic medication on cell numbers in the parietal cortex of macaque monkeys.

Both in vivo and post-mortem investigations have demonstrated smaller volumes of the whole brain and of certain brain regions in individuals with schizophrenia. It is unclear to what degree such smaller volumes are due to the illness or to the effects of antipsychotic medication treatment. Indeed, we recently reported that chronic exposure of macaque monkeys to haloperidol or olanzapine, at doses producing plasma levels in the therapeutic range in schizophrenia subjects, was associated with significantly smaller total brain weight and volume, including an 11.8-15.2% smaller gray matter volume in the left parietal lobe. Consequently, in this study we sought to determine whether these smaller volumes were associated with lower numbers of the gray matter's constituent cellular elements. The use of point counting and Cavalieri's principle on Nissl-stained sections confirmed a 14.6% smaller gray matter volume in the left parietal lobe from antipsychotic-exposed monkeys. Use of the optical fractionator method to estimate the number of each cell type in the gray matter revealed a significant 14.2% lower glial cell number with a concomitant 10.2% higher neuron density. The numbers of neurons and endothelial cells did not differ between groups. Together, the findings of smaller gray matter volume, lower glial cell number, and higher neuron density without a difference in total neuron number in antipsychotic-exposed monkeys parallel the results of post-mortem schizophrenia studies, and raise the possibility that such observations in schizophrenia subjects might be due, at least in part, to antipsychotic medication effects.

Algorithms↗

PubMed2006

Somal size of immunolabeled pyramidal cells in the prefrontal cortex of subjects with schizophrenia.

BACKGROUND: Although the somal volume of Nissl-stained deep layer 3 pyramidal cells is reduced in prefrontal cortex area 9 of subjects with schizophrenia, the subset of large pyramidal cells immunoreactive (IR) for nonphosphorylated neurofilament protein (NNFP) is not. Consequently, we hypothesized that the somal volume of another subset of pyramidal cells immunoreactive for neuronal calcium binding protein-1 (Necab-1) is significantly reduced in schizophrenia. METHODS: We labeled Necab-1-IR pyramidal neurons using immunoperoxidase techniques and estimated the mean somal volume in deep layer 3 of area 9 in 13 matched pairs of control and schizophrenic subjects. Identical studies were conducted for pyramidal neurons immunoreactive for neuronal nuclear protein (Neu-N), which is present in all neurons. RESULTS: In subjects with schizophrenia, neither the mean somal volume of Necab-1-IR pyramidal neurons nor of Neu-N-IR pyramidal neurons was significantly different from control subjects. In addition, the mean somal volume of Neu-N-IR cells was larger than that of Nissl-stained cells in both subject groups, and the magnitude of this difference was greater for the subjects with schizophrenia. CONCLUSIONS: These findings suggest that immunoperoxidase techniques are associated with an overestimation of the volume of labeled neurons. This confound appears to interact with disease state, and thus obscures differences between diagnostic groups.

Adult↗

PubMed2006

Selective elimination of glutamatergic synapses on striatopallidal neurons in Parkinson disease models.

Parkinson disease is a common neurodegenerative disorder that leads to difficulty in effectively translating thought into action. Although it is known that dopaminergic neurons that innervate the striatum die in Parkinson disease, it is not clear how this loss leads to symptoms. Recent work has implicated striatopallidal medium spiny neurons (MSNs) in this process, but how and precisely why these neurons change is not clear. Using multiphoton imaging, we show that dopamine depletion leads to a rapid and profound loss of spines and glutamatergic synapses on striatopallidal MSNs but not on neighboring striatonigral MSNs. This loss of connectivity is triggered by a new mechanism-dysregulation of intraspine Cav1.3 L-type Ca(2+) channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease.

Animals↗

PubMed2005

A framework for two-stage adaptive procedures to simultaneously test non-inferiority and superiority.

In clinical trials it is often desirable to test for non-inferiority and for superiority simultaneously. For such a situation a two-stage adaptive procedure may be advantageous to a conventional single-stage procedure because a two-stage adaptive procedure allows the design of stage II, including the main study objective and sample size, to depend on the outcome of stage I. We propose a framework for designing two-stage adaptive procedures with a possible switch of the primary study objectives at the end of stage I between non-inferiority and superiority. The framework permits control of the type I error rate and specification of the unconditional powers and maximum sample size for each of non-inferiority and superiority objectives. The actions at the end of stage I are predetermined as functions of the stage I observations, thus making specification of the unconditional powers possible. Based on the results at the end of stage I, the primary objective for stage II is chosen, and sample sizes and critical values for stage II are determined.

Clinical Trials as Topic↗

PubMed2005

Analysis of pyramidal neuron morphology in an inducible knockout of brain-derived neurotrophic factor.

BACKGROUND: The messenger ribonucleic acid (mRNA) for brain-derived neurotrophic factor (BDNF), a regulator of pyramidal neuron dendritic spine density during development, is decreased in the prefrontal cortex of subjects with schizophrenia, and the level of BDNF mRNA expression is positively correlated with dendritic spine density in the same subjects. METHODS: To determine whether reduced BDNF mRNA expression might account for decreased spine density in schizophrenia, a knockout of the BDNF gene was induced in mice during embryogenesis or at 12 weeks of age. Quantitative assessments were made of the dendritic arbor of Golgi-impregnated pyramidal neurons in the prelimbic and anterior cingulate cortices in adulthood. RESULTS: Despite an 80% reduction in BDNF mRNA levels in both knockouts, neither spine density nor other dendritic or somal measures were decreased compared with wild-type animals. CONCLUSIONS: A reduction in BDNF expression alone does not seem to be sufficient to alter pyramidal neuron morphology in mice. This finding suggests that other molecular abnormalities are also required to produce the pyramidal neuron dendritic spine abnormalities observed in schizophrenia.

Animals↗

PubMed2005

Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia.

Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD67) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD67 and PV mRNA levels. Decreased BDNF, TrkB, and GAD67 mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD67 mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD67 mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD67 and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD67 mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.

Adult↗

PubMed2005

Drop-the-losers design: normal case.

Drop-the-losers designs are statistical designs which have two stages of a trial separated by a data based decision. In the first stage k experimental treatments and a control are administered. During a transition period, the empirically best experimental treatment is selected for continuation into the second phase, along with the control. At the study's end, inference focuses on the comparison of the selected treatment with the control using both stages' data. Traditional methods used to make inferences based on both stages' data can yield tests with higher than advertised levels of significance and confidence intervals with lower than advertised confidence. For normally distributed data, methods are provided to correct these deficiencies, providing confidence intervals with accurate levels of confidence. Drop-the-losers designs are particularly applicable to biopharmaceutical clinical trials where they can allow Phase II and Phase III clinical trials to be conducted under a single protocol with the use of all available data.

Algorithms↗

PubMed2005

The influence of chronic exposure to antipsychotic medications on brain size before and after tissue fixation: a comparison of haloperidol and olanzapine in macaque monkeys.

It is unclear to what degree antipsychotic therapy confounds longitudinal imaging studies and post-mortem studies of subjects with schizophrenia. To investigate this problem, we developed a non-human primate model of chronic antipsychotic exposure. Three groups of six macaque monkeys each were exposed to oral haloperidol, olanzapine or sham for a 17-27 month period. The resulting plasma drug levels were comparable to those seen in subjects with schizophrenia treated with these medications. After the exposure, we observed an 8-11% reduction in mean fresh brain weights as well as left cerebrum fresh weights and volumes in both drug-treated groups compared to sham animals. The differences were observed across all major brain regions (frontal, parietal, temporal, occipital, and cerebellum), but appeared most robust in the frontal and parietal regions. Stereological analysis of the parietal region using Cavalieri's principle revealed similar volume reductions in both gray and white matter. In addition, we assessed the subsequent tissue shrinkage due to standard histological processing and found no evidence of differential shrinkage due to drug exposure. However, we observed a pronounced general shrinkage effect of approximately 20% and a highly significant variation in shrinkage across brain regions. In conclusion, chronic exposure of non-human primates to antipsychotics was associated with reduced brain volume. Antipsychotic medication may confound post-mortem studies and longitudinal imaging studies of subjects with schizophrenia that depend upon volumetric measures.

Analysis of Variance↗

PubMed2005

Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia.

OBJECTIVE: In a previous study the authors found that dendritic spine density was reduced on prefrontal pyramidal neurons in layer 3 of subjects with schizophrenia. From a neural circuitry perspective, understanding the pathophysiological significance of this finding requires knowledge of whether pyramidal neurons in other cortical layers are similarly affected. The authors' goal was to determine whether their finding in layer 3 was also present in other cortical layers in the same group of subjects with schizophrenia. METHOD: Spine density and other dendritic measures were made for pyramidal neurons in layers 5 and 6 of prefrontal area 46 in the brains of deceased subjects with schizophrenia, subjects with other psychiatric disorders, and normal comparison subjects. RESULTS: None of the dendritic measures for layer 5 or 6 pyramidal neurons differed across the subject groups, but the within-subject differences in spine density between deep layer 3 and layer 5 or 6 pyramidal neurons were significantly greater in the patients with schizophrenia than in the comparison subjects. CONCLUSIONS: These findings are consistent with the idea that prefrontal pyramidal neurons involved in corticocortical and/or thalamocortical connections are preferentially affected in schizophrenia.

Dendritic Spines↗

PubMed2004

Pyramidal cell size reduction in schizophrenia: evidence for involvement of auditory feedforward circuits.

BACKGROUND: Subjects with schizophrenia have decreased gray matter volume of auditory cortex in structural imaging studies and exhibit deficits in auditory sensory processing that might reflect impairments of feedforward and/or feedback circuits within the auditory cortex. Recently, we reported that one component of these circuits, pyramidal cells in deep layer 3 of the auditory association cortex (area 42), has reduced mean somal volume in subjects with schizophrenia. To discriminate between involvement of feedforward and feedback circuit components, we examined pyramidal cell somal volume in layer 3 of primary auditory cortex (feedforward) and layer 5 of auditory association cortex (feedback). METHODS: We estimated somal volumes of pyramidal neurons in deep layer 3 of area 41 and layer 5 of area 42 in subjects with schizophrenia (area 41, n = 16; area 42, n = 18), each of whom was matched to one normal comparison subject for gender, age, and postmortem interval. RESULTS: In deep layer 3 of area 41, mean pyramidal cell somal volume was significantly reduced, by 10.4%. No significant reduction was present in layer 5 of area 42. CONCLUSIONS: Pyramidal cell somal volume is reduced in layer 3 of area 41 and area 42, but not in layer 5 of area 42, of subjects with schizophrenia. This pattern of abnormalities is consistent with impairments of auditory feedforward projection neurons.

Adult↗

PubMed2004

Stereological analysis of the mediodorsal thalamic nucleus in schizophrenia: volume, neuron number, and cell types.

The mediodorsal thalamic nucleus (MD) is the principal relay nucleus for the prefrontal cortex, a brain region thought to be dysfunctional in schizophrenia. Several, but not all, postmortem studies of the MD in schizophrenia have reported decreased volume and total neuronal number. However, it is not clear whether the findings are specific for schizophrenia nor is it known which subtypes of thalamic neurons are affected. We studied the left MD in 11 subjects with schizophrenia, 9 control subjects, and 12 subjects with mood disorders. Based on morphological criteria, we divided the neurons into two subclasses, presumably corresponding to projection neurons and local circuit neurons. We estimated MD volume and the neuron number of each subclass using methods based on modern unbiased stereological principles. We also estimated the somal volumes of each subclass using a robust, but biased, approach. In addition, we investigated the left MD in four cynomolgus monkeys chronically exposed to haloperidol and in four control monkeys in order to assess the possible effects of antipsychotic medications. The three human subject groups did not differ in any of the measures. In addition, no differences were observed between the two groups of monkeys. Thus, these findings do not support the hypothesis that the MD is a locus of pathology in schizophrenia, although they cannot rule out important functional or structural changes in parameters not measured. Like other studies, this investigation is subject to the limitations involved in sampling from a heterogeneous population emphasizing the need to continue to improve the application of robust, unbiased techniques to quantitative studies of this complex brain disorder.

Adult↗

PubMed2003

Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.

Markers of inhibitory neurotransmission are altered in the prefrontal cortex (PFC) of subjects with schizophrenia, and several lines of evidence suggest that these alterations may be most prominent in the subset of GABA-containing neurons that express the calcium-binding protein, parvalbumin (PV). To test this hypothesis, we evaluated the expression of mRNAs for PV, another calcium-binding protein, calretinin (CR), and glutamic acid decarboxylase (GAD67) in postmortem brain specimens from 15 pairs of subjects with schizophrenia and matched control subjects using single- and dual-label in situ hybridization. Signal intensity for PV mRNA expression in PFC area 9 was significantly decreased in the subjects with schizophrenia, predominantly in layers III and IV. Analysis at the cellular level revealed that this decrease was attributable principally to a reduction in PV mRNA expression per neuron rather than by a decreased density of PV mRNA-positive neurons. In contrast, the same measures of CR mRNA expression were not altered in schizophrenia. These findings were confirmed by findings from cDNA microarray studies using different probes. Across the subjects with schizophrenia, the decrease in neuronal PV mRNA expression was highly associated (r = 0.84) with the decrease in the density of neurons containing detectable levels of GAD67 mRNA. Furthermore, simultaneous detection of PV and GAD67 mRNAs revealed that in subjects with schizophrenia only 55% of PV mRNA-positive neurons had detectable levels of GAD67 mRNA. Given the critical role that PV-containing GABA neurons appear to play in regulating the cognitive functions mediated by the PFC, the selective alterations in gene expression in these neurons may contribute to the cognitive deficits characteristic of schizophrenia.

Adult↗

PubMed2003

Estimating times of surgeries with two component procedures: comparison of the lognormal and normal models.

BACKGROUND: Variability inherent in the duration of surgical procedures complicates surgical scheduling. Modeling the duration and variability of surgeries might improve time estimates. Accurate time estimates are important operationally to improve utilization, reduce costs, and identify surgeries that might be considered outliers. Surgeries with multiple procedures are difficult to model because they are difficult to segment into homogenous groups and because they are performed less frequently than single-procedure surgeries. METHODS: The authors studied, retrospectively, 10,740 surgeries each with exactly two CPTs and 46,322 surgical cases with only one CPT from a large teaching hospital to determine if the distribution of dual-procedure surgery times fit more closely a lognormal or a normal model. The authors tested model goodness of fit to their data using Shapiro-Wilk tests, studied factors affecting the variability of time estimates, and examined the impact of coding permutations (ordered combinations) on modeling. RESULTS: The Shapiro-Wilk tests indicated that the lognormal model is statistically superior to the normal model for modeling dual-procedure surgeries. Permutations of component codes did not appear to differ significantly with respect to total procedure time and surgical time. To improve individual models for infrequent dual-procedure surgeries, permutations may be reduced and estimates may be based on the longest component procedure and type of anesthesia. CONCLUSIONS: The authors recommend use of the lognormal model for estimating surgical times for surgeries with two component procedures. Their results help legitimize the use of log transforms to normalize surgical procedure times prior to hypothesis testing using linear statistical models. Multiple-procedure surgeries may be modeled using the longest (statistically most important) component procedure and type of anesthesia.

Algorithms↗

PubMed2002

Reduced pyramidal cell somal volume in auditory association cortex of subjects with schizophrenia.

Subjects with schizophrenia have decreased gray matter volume of auditory association cortex in structural imaging studies, and exhibit deficits in auditory sensory memory processes subserved by this region. In dorsal prefrontal cortex (dPFC), similar in vivo observations of reduced regional volume and working memory deficits in subjects with schizophrenia have been related to reduced somal volume of deep layer 3 pyramidal cells. We hypothesized that deep layer 3 pyramidal cell somal volume would also be reduced in auditory association cortex (BA42) in schizophrenia. We used the nucleator to estimate the somal volume of pyramidal neurons in deep layer 3 of BA42 in 18 subjects with schizophrenia, each of whom was matched to one normal comparison subject for gender, age, and post-mortem interval. For all subject pairs, somal volume of pyramidal neurons in deep layer 3 of dPFC (BA9) had previously been determined. In BA42, somal volume was reduced by 13.1% in schizophrenic subjects (p=0.03). Reductions in somal volume were not associated with the history of antipsychotic use, alcohol dependence, schizoaffective disorder, or death by suicide. The percent change in somal volume within-subject pairs was highly correlated between BA42 and BA9 (r=0.67, p=0.002). Deep layer 3 pyramidal cell somal volume is reduced in BA42 of subjects with schizophrenia. This reduction may contribute to impairment in auditory function. The correlated reductions of somal volume in BA42 and BA9 suggest that a common factor may affect deep layer 3 pyramidal cells in both regions.

Adult↗

PubMed2002

A meta-analytic approach to an integrated summary of efficacy: a case study of becaplermin gel.

This paper presents a case study involving a meta-analytic approach for an integrated summary of efficacy based upon four phase II and III clinical trials that comprised the basis for a Biologics License Application to the U.S. Food and Drug Administration for approval of becaplermin gel. There were substantial variations in observed response rates across the four studies that were of concern to regulatory agencies. Due to these variations and because there were various treatment combinations in the four trials, standard statistical methods for an integrated analysis of efficacy were problematic. A meta-analytic model that focused on the variations of concern was employed to permit a suitable integrated analysis. The resulting integrated analysis clarified response rate variability and provided accurate estimates of treatment effects based upon the four clinical trials. While this meta-analysis was viewed by neither regulators nor the sponsor as a confirmatory analysis, it was seen by both regulators and sponsor as strongly supportive of the efficacy of becaplermin gel.

Anticoagulants↗

PubMed2002

Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia.

In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABA(A) receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the alpha(2) subunit of the GABA(A) receptor is preferentially localized at pyramidal neuron AIS, we quantified alpha(2) subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of alpha(2)-labeled AIS per mm(2) in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of alpha(2)-labeled AIS was negatively correlated (r = -0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABA(A) receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron-pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.

Adult↗