Brain pH has a significant impact on human postmortem hippocampal gene expression profiles.

Studies of neurobiological disorders in the brain, including schizophrenia, rely on the use of postmortem brain tissues, in which an understanding of the effects of various pre- and postmortem variables on gene expression is critical. In several different brain regions, pH has been shown to have a large effect on postmortem brain gene expression patterns. One region that has not yet been evaluated in such studies is the hippocampus, a region often implicated in schizophrenia research. In the present study, we show that postmortem brain pH is similar across different brain regions. Brain pH accounted for greater variation in hippocampal gene expression profiles than any other parameter evaluated, including gender and schizophrenia. The predictive value of brain pH in an independent sample set was also greater than the disease, demonstrating that pH represents one of the most important control parameters in human postmortem gene expression studies in schizophrenia.

Differential modulation of gene expression in the NMDA postsynaptic density of schizophrenic and control smokers.

Nicotine is known to induce the release of multiple neurotransmitters, including glutamate and dopamine, through activation of nicotinic receptors. Gene expression in the N-methyl-d-aspartate postsynaptic density (NMDA-PSD), as well as other functional groups, was compared in postmortem hippocampus of schizophrenic and nonmentally ill smokers and nonsmokers utilizing a microarray and quantitative RT-PCR approach. The expression of 277 genes was significantly changed between all smokers and nonsmokers. Specific gene groups, most notably genes expressed in the NMDA-PSD, were prevalent among these transcripts. Analysis of the interaction between smoking and schizophrenia identified several genes in the NMDA-PSD that were differentially affected by smoking in patients. The present findings suggest that smoking may differentially modulate glutamatergic function in schizophrenic patients and control subjects. The biological mechanisms underlying chronic tobacco use are likely to differ substantially between these two groups.

Which duration of postsaccadic slowing identifies anticipatory saccades during smooth pursuit eye movements?

Increased frequency of anticipatory saccades during smooth pursuit eye movements is a potential marker of genetic risk for schizophrenia. Postsaccadic slowing criteria are used to separate anticipatory from other types of saccades. However, the necessary duration of slowed pursuit required to identify an anticipatory saccade remains undetermined. We explored the effect of various postsaccadic slowing duration criteria on effect size in a comparison of younger and older schizophrenic and normal adults. For large anticipatory saccades, varying the duration of postsaccadic slowing criteria did not notably change effect size. For smaller leading saccades, a limited 50-ms duration postsaccadic slowing criterion produced the largest effect size (1.54), and maintained a similar effect size across a broad age range. Leading saccades with a limited duration postsaccadic slowing criteria are a possible marker of genetic risk for schizophrenia.

Diagnosis and treatment of psychiatric disorders in children with a schizophrenic parent.

Many children of a schizophrenic parent may inherit a portion of the genetic risk factors for schizophrenia. The frequency of DSM-IV psychopathology in children of a schizophrenic parent and the frequency and type of mental health treatment accessed by these youths is not well understood. Twenty-eight adults with schizophrenia were identified and 43 of their 6--15 year old children recruited. Clinical diagnoses, based on a structured DSM-IV interview; severity of impairment, based on the Child Global Assessment Scale; and treatment histories were obtained. Seventy-four per cent of children-with-a-schizophrenic-parent met diagnostic criteria for a current Axis I psychiatric disorder. The most common diagnostic categories included attention deficit/hyperactivity disorder (40%), any anxiety disorder (23%), and any depressive disorder (12%). Psychosis was present in 9% of this childhood sample. Of those children with a psychiatric diagnosis, 47% demonstrated current moderate or severe impairment. Approximately half of the children had received mental health evaluations and 26% had experienced at least one psychiatric medication trial. Children-with-a-schizophrenic-parent have frequent, often impairing, psychiatric problems. Despite this high prevalence, mental health evaluation and treatment is of similar frequency and type to other at-risk populations. The effectiveness and appropriateness of standard treatments remain unstudied in children-with-a-schizophrenic-parent.

Smoking and mental illness.

Patients with mental illness have a higher incidence of smoking than the general population and are the major consumers of tobacco products. This population includes subjects with schizophrenia, manic depression, depression, posttraumatic stress disorder (PTSD), attention-deficit disorder (ADD), and several other less common diseases. Smoking cessation treatment in this group of patients is difficult, often leading to profound depression. Several recent findings suggest that increased smoking in the mentally ill may have an underlying biological etiology. The mental illness schizophrenia has been most thoroughly studied in this regard. Nicotine administration normalizes several sensory-processing deficits seen in this disease. Animal models of sensory deficits have been used to identify specific nicotinic receptor subunits that are involved in these brain pathways, indicating that the alpha 7 nicotinic receptor subunit may play a role. Genetic linkage in schizophrenic families also supports a role for the alpha 7 subunit with linkage at the alpha 7 locus on chromosome 15. Bipolar disorder has some phenotypes in common with schizophrenia and also exhibits genetic linkage to the alpha 7 locus, suggesting that these two disorders may share a gene defect. The alpha 7 receptor is decreased in expression in schizophrenia. [(3)H]-Nicotine binding studies in postmortem brain indicate that high-affinity nicotinic receptors may also be affected in schizophrenia.

The prevalence of reversible airway obstruction in professional football players.

PURPOSE: To determine the prevalence of reversible airway obstruction in a group of professional football training camp participants. METHODS: All attendees at a Canadian Football League team rookie preseason training camp were invited to participate in a protocol designed to elicit symptoms and signs of reversible airway obstruction (asthma) during the initial preparticipation examination. Those agreeing to the protocol completed a questionnaire containing standardized inquiries about a past history of asthma and the presence of symptoms. Participants then underwent spirometry testing to determine lung function before and after receiving a standardized dose of bronchodilator medication. Players showing evidence of airway obstruction during initial testing and still on the team roster underwent repeat spirometry testing and formal pulmonary function testing during the football season. The follow-up pulmonary function tests were performed to determine those that might benefit from treatment for asthma. RESULTS: Nineteen of 34 (56%) players agreeing to participate had significant reversible airway obstruction as defined by a 12% or greater reversibility in forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR), and/or forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF 25-75). In most participants, the diagnosis was made on the basis of spirometry alone. Of those testing positive during initial inquiry, 88% remained positive on repeat spirometry, and 73% had reversible airway obstruction during more stringently controlled hospital-based pulmonary function testing. Those players treated for previously undiagnosed asthma noted an improvement in subjective athletic performance during the football season. CONCLUSION: Based on the remarkably high prevalence of undiagnosed asthma in this group, it may prove worthwhile to test elite football players using lung function parameters.

NURR1 mutations in cases of schizophrenia and manic-depressive disorder.

Transgenic mice lacking the nuclear orphan transcription factor Nur-related receptor 1 (Nurr1) fail to develop mesencephalic dopamine neurons. There is a highly homologous NURR1 gene in humans (formerly known as NOT) which therefore constitutes a good candidate gene for neurologic and psychiatric disorders with an involvement of the dopamine neuron system, such as Parkinson's disease, schizophrenia, and manic-depression. By direct sequencing of genomic DNA, we found two different missense mutations in the third exon of NURR1 in two schizophrenic patients and another missense mutation in the same exon in an individual with manic-depressive disorder. All three mutations caused a similar reduction of in vitro transcriptional activity of NURR1 dimers of about 30-40%. Neither of these amino acid changes, nor any sequence changes whatsoever, were found in patients with Parkinson's disease or control DNA material of normal populations. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:808-813, 2000.

Smooth pursuit eye movements in schizophrenia and attentional dysfunction: adults with schizophrenia, ADHD, and a normal comparison group.

BACKGROUND: Smooth pursuit eye movement (SPEM) abnormalities are found in schizophrenia. These deficits often are explained in the context of the attentional and inhibitory deficits central to schizophrenia psychopathology. It remains unclear, however, whether these attention-associated eye movement abnormalities are specific to schizophrenia or are a nonspecific expression of attentional deficits found in many psychiatric disorders. Adult attention-deficit/hyperactivity disorder (ADHD) is an alternative disorder with chronic attentional and inhibitory dysfunction. Thus, a comparison of SPEM in adult schizophrenia and adult ADHD will help assess the specificity question. METHODS: SPEM is recorded during a 16.7 degrees per second constant velocity task in 17 adults with ADHD, 49 adults with schizophrenia, and 37 normal adults; all groups included individuals between ages 25-50 years. RESULTS: Smooth pursuit gain and the frequency of anticipatory and leading saccades are worse in schizophrenic subjects, with normal and ADHD subjects showing no differences on these variables. CONCLUSIONS: Many attention-associated SPEM abnormalities are not present in most subjects with ADHD, supporting the specificity of these findings to the attentional deficits seen in schizophrenia.

Eye movement task measures inhibition and spatial working memory in adults with schizophrenia, ADHD, and a normal comparison group.

Schizophrenia and attention deficit/hyperactivity disorder (ADHD) are both associated with deficits in inhibition and working memory, although in ADHD the working memory deficit is hypothesized to be secondary to the inhibitory deficit. This similarity in cognitive processes has been paralleled by similarities across the two groups in the performance of working memory and inhibition tasks. The delayed oculomotor response task is an alternative task, which may allow greater separation of working memory from inhibitory components, and thus its use may provide additional information on primary vs. secondary deficits in these disorders. Ten young adult ADHD sufferers, 10 schizophrenic subjects, and 10 normal subjects were matched on age, gender, and education. Eye movements were recorded during delayed oculomotor response tasks with 1- and 3-s delays. Both the ADHD and the schizophrenic subjects demonstrated dis-inhibition (an increased percentage of premature saccades); however only schizophrenic subjects demonstrated an impaired working memory (decreased spatial accuracy of the remembered saccade). The results are consistent with the hypothesis that working memory is a primary deficit in schizophrenia, but secondary to the inhibitory deficit in ADHD.

The P50 auditory event-evoked potential in adult attention-deficit disorder: comparison with schizophrenia.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and schizophrenia are both conceptualized as disorders of attention. Failure to inhibit the P50 auditory event-evoked response, extensively studied in schizophrenia, could also occur in ADHD patients, if these two illnesses have common underlying neurobiological substrates. METHODS: This study examined the inhibition of the P50 auditory event-evoked potential in 16 unmedicated adults with ADHD, 16 schizophrenic outpatients, and 16 normal control subjects. Auditory stimuli were presented in a paired stimulus, conditioning-testing paradigm. RESULTS: The amplitude of initial or conditioning P50 response did not differ between the three groups; however, significant effects of psychiatric diagnosis on the amplitude of the test response and the ratio of the test to the conditioning response amplitudes were observed. Schizophrenic patients' P50 ratios and test amplitudes were higher than both the ADHD and normal groups. CONCLUSIONS: Adults with ADHD do not have the inhibitory deficit seen in patients with schizophrenia, suggesting that the mechanism of attentional disturbance in the two illnesses may be fundamentally different.

Inhibitory neurophysiological deficit as a phenotype for genetic investigation of schizophrenia.

Many investigators have proposed that biological endophenotypes might facilitate the genetic analysis of schizophrenia. A deficit in the inhibition of the P50 evoked response to repeated auditory stimuli has been characterized as a neurobiological deficit in schizophrenia. This deficit is linked to a candidate gene locus, the locus of the alpha7-nicotinic cholinergic receptor subunit gene on chromosome 15q14. Supportive evidence has been found by other investigators, including: 1) linkage of schizophrenia to the same locus; 2) linkage of bipolar disorder to the locus; and 3) replication of the existence of this neurobiological deficit and its relation to broader neuropsychological deficits in schizophrenia. It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses.

Familial transmission of risk factors in the first-degree relatives of schizophrenic people.

Schizophrenia is a complex illness with multiple pathophysiologic factors that contribute to its psychopathology. One strategy to identify these factors is to observe them in isolation from each other, by characterizing their expression in the relatives of schizophrenic probands. By Mendel's second law, each genetic factor should be independently distributed in a sibship, so that each can be observed by itself, uncomplicated by the general problems of the illness. Such independently distributed phenotypes are obviously useful for genetic analyses; however, they can also be considered together, to model how various brain dysfunctions may combine to produce psychoses. In addition to a sensory gating deficit linked to the alpha 7-nicotinic acetylcholine receptor locus, schizophrenics and their families have a number of other deficits, including decreased hippocampal volume on magnetic resonance images and increased plasma levels of the dopamine metabolite homovanillic acid. Although such research is far from complete, a heuristic model combining a sensory gating deficit, decreased hippocampal neuron capacity, and increased dopaminergic neurotransmission is consonant with current understanding of the neuropsychology of schizophrenia.

The effects of age on a smooth pursuit tracking task in adults with schizophrenia and normal subjects.

BACKGROUND: Performance during a smooth pursuit eye movement (SPEM) task has been proposed as a marker of genetic risk for schizophrenia, although the precise component of SPEM tracking most associated with genetic risk remains undetermined. Normal adult aging is associated with deterioration on SPEM tasks; it remains unclear whether investigations of SPEM abnormalities will allow inclusion of older subjects in genetic studies. This study examines 1) the effect of normal aging on several components of SPEM performance; and 2) whether schizophrenic-normal differences found in young adults continue over a broad adult age span. METHODS: SPEM was recorded during a 16.7 degrees per sec constant velocity task in 64 normal adults, ages 18 to 79 years, and 58 schizophrenic subjects, ages 18 to 70 years. RESULTS: Smooth pursuit gain, the percent of total eye movements due to catch-up saccades, the frequency of large anticipatory saccades, and the frequency of leading saccades all deteriorate with increasing age. After correction for age, schizophrenic to control differences persist on most eye movement variables with the largest effect sizes for leading saccades (1.56) and smooth pursuit gain (1.17). CONCLUSIONS: The tendency to use saccades to anticipate target motion, even in small steps (leading saccades), deserves further attention as a potential marker useful in genetic analyses.

Amplitude criteria and anticipatory saccades during smooth pursuit eye movements in schizophrenia.

Increased frequency of anticipatory saccades during smooth pursuit eye movements is a potential marker of genetic risk for schizophrenia even in the absence of clinical symptomology. The operational definition of anticipatory saccades has often included an amplitude criterion; however, these amplitude criteria have often differed across studies. This study reports on the effect of varying amplitude criteria on the effect size in a comparison of 29 schizophrenic adults and 29 normal subjects during a 16.7 degrees/s constant velocity task. The inclusion of small amplitude anticipatory saccades, with amplitudes of 1-4 degrees, consistently increased effect size (largest effect size = 1.61). The inclusion of large anticipatory saccades, with amplitudes of 4 degrees or greater, had an inconsistent impact on effect size. The separation of anticipatory saccades into leading saccades (anticipatory saccades with amplitude 1-4 degrees) and large anticipatory saccades (amplitude > 4 degrees) deserves further exploration.

Elementary phenotypes in the neurobiological and genetic study of schizophrenia.

This review describes the strategy of using elementary phenotypes for neurobiological and genetic linkage studies of schizophrenia. The review concentrates on practical aspects of selecting the phenotype and then understanding the confounds in its measurement and interpretation. Examples from the authors' studies of deficits in P50 inhibition and smooth pursuit eye movement dysfunction are presented. These two phenotypes share considerable similarity in their neurobiology, including a similar response to nicotine. They also appear to co-segregate with the genetic risk for schizophrenia as autosomal co-dominant phenotypes. Although most schizophrenic patients inherit these abnormalities unilinealy, i.e., from one parent, apparent bilineal inheritance produces a more severe illness, observed clinically as childhood-onset schizophrenia. The initial study showing linkage of the P50 deficit to the chromosome 15q14 locus of the alpha 7-nicotinic acetylcholine receptor is an example of the potential usefulness of these phenotypes for combined genetic and neurobiological study of schizophrenia.

Evidence for bilineal inheritance of physiological indicators of risk in childhood-onset schizophrenia.

Childhood-onset schizophrenia is proposed to be associated with increased genetic loading compared with adult-onset schizophrenia because of its earlier age of onset and generally greater severity of symptoms. Diminished suppression of P50 auditory evoked responses to repeated stimuli and elevated anticipatory saccades during smooth pursuit eye movements are markers of genetic risk that are found in members of families with schizophrenia even in the absence of the full clinical disorder and appear to be transmitted in a single gene autosomal dominant fashion. Adult-onset schizophrenia is generally associated with one parent who demonstrates abnormal P50 sensory gating and elevated anticipatory saccades and one parent who is normal on the physiologic measures (i.e., unilineal inheritance). This study investigates whether childhood-onset schizophrenia is similarly unilineal or is associated with the inheritance of genetic risk factors from both parents (i.e., bilineal inheritance). Ten childhood-onset schizophrenic probands and their parents were studied. Their P50 sensory gating and anticipatory saccades were compared with adult-onset schizophrenic probands and their parents. Bilineality, measured as physiological impairment in both parents, occurred more frequently in childhood-onset probands than in adult-onset probands for both P50 sensory gating deficits (60% versus 13%) and elevated anticipatory saccades (60 versus 0%). Additionally, childhood-onset schizophrenic probands performed more poorly than adult-onset probands on the anticipatory saccade measure. This physiological evidence suggests that childhood-onset schizophrenia may be associated with increased genetic loading because of contributions of genetic risk from both parents.

Deficient cancellation of the vestibular ocular reflex in schizophrenia.

Schizophrenia has long been associated with difficulties in visual tracking of a moving object. Deficits are most notable in tracking tasks that require inhibition of saccades during active smooth pursuit. In order to assess whether there is a more global problem in inhibition of other eye movement systems while the smooth pursuit system is active, this study examined cancellation of the vestibular ocular reflex (VOR). Cancellation of the VOR occurs in a task in which the subject is rotated while looking at a target that is also being rotated. This requires the subject to use the pursuit system to override the VOR, maintain the eye at a stable location within the orbit, and thus retain visual gaze upon the target. Thirteen individuals with schizophrenia and 15 normals were assessed during clockwise rotation at 60 degrees s-1. Schizophrenic subjects had a significant increase in counterclockwise slow velocity eye movements, suggesting an impaired ability to cancel the VOR. Cancellation of the VOR is thus another example of a breakthrough of an alternative eye movement system while the smooth pursuit system is active. Because of the simplicity of the VOR and its suitability for animal modeling, investigation of this phenomenon may delineate more precisely the mechanisms of visual tracking dysfunction in schizophrenia.

Anticipatory saccades during smooth pursuit eye movements and familial transmission of schizophrenia.

BACKGROUND: Smooth pursuit eye movement (SPEM) abnormalities are a putative marker of genetic risk for schizophrenia. Accurate SPEM performance requires the subject to activate neural systems responsible for smooth pursuit tracking, while simultaneously suppressing activity of neurons responsible for saccadic movements that would move the eye ahead of the target. This study examined whether specific aspects of SPEM dysfunction cosegregate with genetic risk in parents of schizophrenic probands. METHODS: Eighteen probands and their parents had SPEM recorded. Parents with an ancestral history of schizophrenia were hypothesized to be more likely than their spouses without such a history to carry a genetic risk for schizophrenia. RESULTS: Ten families had a single parent with a positive ancestral history for schizophrenia. The frequency of anticipatory saccades, which were mostly small, and the fraction of total eye movement that they represented were the only measures that differentiated the more likely genetic carrier parents in these families from their spouses and age-matched normals. CONCLUSIONS: Failure to suppress saccadic anticipation of target motion during smooth pursuit appears an aspect of SPEM dysfunction related to presumed genetic risk for schizophrenia.

Familial transmission of two independent saccadic abnormalities in schizophrenia.

Difficulties with inhibiting inappropriate responses, i.e. disinhibition, and problems with spatial memory are both presumed to be a part of the phenotypic expression of the genetic risk for schizophrenia. Schizophrenic probands are impaired on saccadic eye movement tasks which require (a) response inhibition to prepotent stimuli and (b) generation of an accurate response to a remembered or calculated spatial location, but it is unknown how these deficits are inherited. Sixteen schizophrenic probands, their 32 parents, and two normal control groups completed a delayed oculomotor response and an antisaccade task. The parents with a positive ancestral family history for chronic psychosis (n = 8) were presumed to be more likely than their family history-negative spouses to be genetic carriers for schizophrenia. Probands and their positive family history parents had more failures of response inhibition than did normal control groups. However, it was the probands and their negative family history spouses who demonstrated impaired accuracy of the remembered- or antisaccades. Disinhibition may be closely tied to a specific genetic risk for schizophrenia. However, a second familial factor related to the maintenance or manipulation of spatial information may also contribute to the genetic risk of the full clinical disorder.

How controlled stress affects healing tissues.

Restoration of a patient's full range of motion, strength, and function are the primary goals of occupational and physical therapy. Immobilization of normal connective tissue leads to biochemical, biomechanical, and physiologic changes within a week. These changes are magnified in the presence of trauma or edema, and they may create permanent damage if not addressed swiftly and properly. This is best accomplished by applying specific types of stress to the involved and associated structures at optimal intervals during the rehabilitation process. Load must be applied at adequate intensity and duration to successfully affect the viscous property of connective tissue. This is necessary to effect permanent elongation of the restricted tissues. Early controlled motion is vital to prevent the negative changes associated with immobilization and to maintain normal viscoelasticity and homeostasis of connective tissue. Hand therapists must have a thorough understanding of the changes associated with injured structures. Only then can they provide optimal stress delivery to facilitate restoration of function.