William S. Stone

Individual differences in aging: Behavioral and neurobiological correlates

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation.

Fine‐tuning of neuronal connections during development is regulated through environmental interactions. Some fine‐tuning occurs through changes in gene expression and/or epigenetic gene‐specific DNA methylation states. DNA methylation occurs by transfer of a methyl group from S‐adenosyl methionine to cytosine residues in the dinucleotide sequence CpG. Although CpG sequences spread throughout the genome are usually heavily methylated, those occurring in CpG islands in the promoter regions of genes are less methylated. In most cases, the extent of DNA methylation correlates with the extent of gene inactivation. Other known epigenetic mechanisms include histone deacetylation and chromatin remodeling, RNA inhibition, RNA modification, and DNA rearrangement. Exposure memory expressed as epigenetic DNA modifications allows genomic plasticity and short‐term adaptation of each generation to their environment. Environmental factors that affect DNA methylation include diet, proteins, drugs, and hormones. Induced methylation changes may produce altered gene response upon subsequent hormonal stimulation. The gene‐specific DNA methylation state may be preserved upon transmission through mitosis and meiosis. An increasing amount of data implicates a role for DNA methylation in multi‐factorial psychiatric disorders. For example, l‐methionine treatment can exacerbate psychosis; while valproate, a drug producing hypomethylated DNA, reduces such symptoms. Hypermethylation of the promoter region of the RELN gene correlates with reduced gene expression. This genes protein Reelin, which is necessary for neuronal migration and synaptogenesis, is reduced in schizophrenia and bipolar disorder, suggesting hypermethylation of the promoter region in these disorders. Some evidence implicates methylation of the promoter regions of the DRD2 and HTR2A genes in schizophrenia and mood disorders as well. DNA methylation usually increases with age, although hypomethylation of the promoter region of the amyloid A4 precursor gene during aging may play a role in Alzheimers disease. More studies are needed to define the role of methylomics and other epigenetic phenomena in the nervous system.

Scopolamine- and morphine-induced impairments of spontaneous alternation performance in mice : reversal with glucose and with cholinergic and adrenergic agonists

Administration of epinephrine and glucose, as well as drugs that influence cholinergic and opiate systems, can enhance or impair memory. The present experiments examined the possibility that peripheral glucose administration might reverse scopolamine- and morphine-induced impairments in a spontaneous alternation task. Mice received all drug administrations 30 min before testing. Scopolamine-induced (3 mg/kg) deficits in alternation performance were reversed by glucose (100 and 250 mg/kg), amphetamine (1 mg/kg), epinephrine, physostigmine, and oxotremorine (each 0.1 mg/kg). Morphine (10 mg/kg) also impaired spontaneous alternation performance, and glucose (100 and 300 mg/kg) reversed this impairment as well. These findings are consistent with the view that central cholinergic systems, possibly under inhibitory opiate regulation, may contribute to glucose and epinephrine effects on memory storage.

Evaluation of Functionally Meaningful Measures for Clinical Trials of Cognition Enhancement in Schizophrenia

OBJECTIVE Because reduction of psychotic symptoms in schizophrenia does not result in adequate community functioning, efforts have shifted to other areas, such as cognitive impairment. The U.S. Food and Drug Administration requires that drugs for cognition enhancement in schizophrenia show improvement on two distinct outcome measures in clinical trials: an accepted cognitive performance battery and a functionally meaningful coprimary measure. The authors examined the reliability, validity, and practicality of functionally meaningful measures. METHOD In this four-site validation study, schizophrenia patients were assessed at baseline (N=166) and 4 weeks later (N=144) on performance-based (Independent Living Scales, Test of Adaptive Behavior in Schizophrenia [TABS], and UCSD Performance-based Skills Assessment [UPSA]) and interview-based (Cognitive Assessment Interview and Clinical Global Impression Scale for Cognition) candidate coprimary measures. In addition, cognitive performance, community functioning, and clinical symptoms were assessed. Both full and short forms of the performance-based measures were evaluated. RESULTS All measures were well tolerated by patients, had adequate test-retest reliability, and showed good utility as a repeated measure. Measures differed in their correlation with cognitive performance, with performance-based measures having stronger correlations than interview-based measures. None of the measures had notable floor or ceiling effects or missing data. CONCLUSIONS Among the full-form measures, the UPSA was judged to have the strongest overall properties. Among the short forms, the TABS and UPSA appeared to have the strongest features. Use of the short forms saves time, but at the cost of lower test-retest reliability and weaker correlations with cognitive performance.

Attenuation of scopolamine-induced amnesia in mice

Numerous studies suggest that age-related declines in memory storage are related to impairment of central cholinergic systems. Scopolamine, a muscarinic cholinergic antagonist, has been used with young humans and other animal species as a model of the cognitive impairment that often accompanies normal and pathological aging. The present study examined whether amnesia induced by scopolamine could be counteracted in mice by arecoline, a cholinergic agonist, or by other drugs, epinephrine or glucose, which have been found to enhance memory in aged rodents and humans. Young mice were administered scopolamine (3 mg/kg, IP) or saline prior to training on an inhibitory avoidance apparatus. Immediately after training, animals received injections of epinephrine (0.01, 0.05, 0.1, and 0.2 mg/kg), glucose (10, 100, and 250 mg/kg), arecoline (0.5, 1, 2, 5, 10, and 20 mg/kg), or saline. The results indicate that pre-training scopolamine reliably impaired retention assessed in test trials 48 h after training. This impairment was not attentuated by any post-training dose of arecoline; however, immediate post-training injections of both epinephrine (at 0.05 mg/kg) and glucose (at 100 mg/kg) significantly reduced the amnesia. Neither of these drugs was effective if injections were delayed by 1 h after training. These results support the value of scopolamine as a model of age-related memory impairments, but suggest further that these memory deficits may be particularly susceptible to attenuation with non-cholinergic treatments.

Genome-Wide Linkage Analyses of 12 Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia

OBJECTIVE The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated. METHOD Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 single-nucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigree-wide regression methods. RESULTS Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degraded-stimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23). CONCLUSIONS Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results.

Safety and proof of principle study of cerebellar vermal theta burst stimulation in refractory schizophrenia.

BACKGROUND Early invasive electrical stimulation studies suggested that enhancement of cerebellar vermal activity might prove valuable in symptomatic treatment of refractory neuropsychiatric diseases via modulation of emotion and affect. This proof of principle study aimed to test this hypothesis using noninvasive brain stimulation, and to explore the safety of this protocol in schizophrenia. METHODS Eight treatment-refractory patients with schizophrenia underwent ten sessions of intermittent theta burst stimulation (TBS) to the cerebellar vermis using MRI-guided transcranial magnetic stimulation (TMS). Assessments included side effect questionnaires, cardiovascular monitoring, psychiatric evaluations and comprehensive neuropsychological testing before and after TBS and at one-week follow-up. RESULTS Overall, TBS was tolerated well with mild side effects primarily comprising neck pain and headache. No serious adverse events occurred. Diastolic blood pressure (BP) showed mild decreases for five minutes post-TBS; no significant changes were detected for systolic BP or pulse. PANSS negative subscale showed significant improvements following TBS and during the follow-up. Calgary Depression Scale and self-report visual analog scales for Happiness and Sadness pointed to significant mood elevation. Neuropsychological testing revealed significantly fewer omissions in working memory and interference conditions of a Continuous Performance Test, a longer spatial span and better delay organization on the Rey-Osterrieth Complex Figure during follow-up. No significant worsening in psychiatric or neuropsychological measures was detected. CONCLUSIONS Theta burst stimulation of the cerebellar vermis is safe and well-tolerated, while offering the potential to modulate affect, emotion and cognition in schizophrenia. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.

Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies

BACKGROUND Substantial evidence now shows that the genetic vulnerability to schizophrenia can be manifested clinically in first-degree relatives of people with schizophrenia, even without the full manifestations of the disorder. One pattern of problems observed involves the combination of negative symptoms and neuropsychological deficits. We have investigated whether a low dose of a novel antipsychotic medication, risperidone, could attenuate these clinical problems in non-psychotic, first-degree relatives, and report here findings from our first 4 cases. METHODS Twelve adults who were first-degree relatives of patients with schizophrenia were evaluated for the presence of negative symptoms and neuropsychological deficits (in attention and working memory, long-term verbal memory and executive functions). Four subjects who met our predetermined criteria, and who did not demonstrate medical contraindications, were enrolled in a 6-week trial of risperidone. Clinical and medical measures were assessed before, during and after treatment. Doses of risperidone started at 0.25 mg and were increased to 1.0-2.0 mg/day. RESULTS These subjects showed substantial reductions in negative symptoms, and one subject showed modest reductions. All four subjects showed substantial improvements on some tests of attention and working memory. Side effects of risperidone were temporary and mainly mild. CONCLUSIONS These initial findings support two conclusions. First, clinical deficits in non-psychotic first-degree relatives of people with schizophrenia are identifiable, and to a significant extent, reversible. Second, risperidone may eventually serve as an effective treatment for people whose lives are impaired by similar or related problems.

Glucose enhancement of 24-h memory retrieval in healthy elderly humans.

When administered soon before or after training, glucose facilitates memory in rodents and in several populations of humans, including healthy elderly people. Thus, glucose appears to enhance memory formation in a time- and dose-dependent manner. By assessing the effects of glucose at the time of memory tests, the present experiment examined the role of glucose on memory retrieval in healthy elderly people. On four sessions separated by a week, glucose or saccharin were administered immediately before hearing a narrative prose passage, as in previous experiments, or immediately before being tested for recall of the passage (24 h after training). Subjects recalled significantly more information after glucose ingestion than after saccharin ingestion whether the glucose was given before acquisition or memory tests. In addition, recall was significantly better in the preacquisition glucose condition relative to recall in the retrieval glucose condition. These findings provide evidence that glucose enhances both memory storage and retrieval.

Neuroendocrine effects on memory in aged rodents and humans

Considerable evidence indicates that epinephrine regulates memory storage processing in young animals. Recent findings suggest that hyperglycemia subsequent to epinephrine release or injection may mediate the hormones effects on memory. This paper reviews findings demonstrating that epinephrine and glucose treatments attenuate age-related memory impairments in rodents and humans. Additional results suggest that, in aged human and animal subjects, poor glucose regulation predicts memory performance of individual subjects.