Modulation of Cerebral Blood Flow in the Human Auditory Cortex During Speech: Role of Motor-to-sensory Discharges

To investigate mechanisms of audio-vocal interactions in the human brain, we studied the effect of speech output on modulation of neuronal activity in the auditory cortex. The modulation was assessed indirectly by measuring changes in cerebral blood flow (CBF) during unvoiced speech (whispering). Using positron emission tomography (PET), CBF was measured in eight volunteers as they uttered syllables at each of seven rates (30, 50, 70, 90, 110, 130 or 150/min) during each of the seven 60–s PET scans. Low-intensity white noise was used throughout scanning to mask auditory input contingent on the whispering. We found that, as a function of the increasing syllable rate, CBF increased in the left primary face area, the upper pons, the left planum temporale and the left posterior perisylvian cortex. The latter two regions contain secondary auditory cortex and previously have been implicated in the processing of speech sounds. We conclude that, in the absence of speech-contingent auditory input, the modulation of CBF in the auditory cortex is mediated by motor-to-sensory discharges. As such, it extends our previous findings of oculomotor corollary discharges to the audio-vocal domain.     

Immunohistochemical Localization of Phosphorylated Glial Fibrillary Acidic Protein in the Prefrontal Cortex and Hippocampus from Patients with Schizophrenia, Bipolar Disorder, and Depression

Increasingly, abnormalities of glial cell function have been implicated in pathological studies of the major mental illnesses (schizophrenia, bipolar disorder, and major depression). In a recent proteomic study, four isoforms of astrocytic glial fibrillary acidic protein (GFAP) were decreased in one or more of these diseases. In the current study, we sought to determine the immunohistochemical localization of phosphorylated GFAP (pGFAP) in the prefrontal cortex and hippocampus and to describe possible disease-related changes in the distribution of pGFAP containing astrocytes. In the prefrontal cortex, interlaminar astrocytes in layer I and stellate astrocytes in layers II and VI were labeled. Labeled cells were also present adjacent to blood vessels in the gyral white matter and in underlying white matter generally. In the hippocampus, labeled cells were present in the polymorphic layer of the dentate gyrus. In the prefrontal cortex, schizophrenia and major depression were characterized by decreased labeling of astrocytes adjacent to blood vessels. There were no significant differences between the diagnostic groups in the other prefrontal layers or in the hippocampus. These results suggest that reduced numbers or functional regulation of pGFAP containing astrocytes occurs in schizophrenia and major depression. The mechanism by which this deficit occurs is not known, but it may adversely effect the regulation of neuronal metabolism, communication, and response to injury.     

Motor impairment in Wilson's disease, II: slowness of speech

The maximal syllable production rate (MSPR) and the ability to reproduce a given target frequency in the 1 to 8 Hz range by repeating the short syllable "ta" was tested in 20 patients with Wilson's disease (WD) and 20 normal subjects. MSPR was significantly reduced in the WD-patients. In the 1 to 5 Hz range normal subjects as well as WD-patients tended to produce slightly higher frequencies than the target frequencies. This hastening was maximal in normals between 4 to 5 Hz whereas in the WD-patients hastening mainly occurred between 3 to 4 Hz. The test results showed a considerable variation across the patients. This variation can be interpreted on the basis of the theory of coupled oscillators. Comparison of speech and finger movements revealed a highly significant correlation between MSPR and the highest possible frequency of voluntary alternating index finger movements. As an application of the presented test treatment effects on speech movements were demonstrated.     

Charcot-Marie-Tooth disease in northern Sweden: an epidemilogical and clinical study

One hundred four cases of Charcot-Marie-Tooth desease (CMT) in 52 families were identified within a defined area in northern Sweden corresponding to a prevalence rate of 20.1 cases per 100000. The distribution of cases was not uniform. The prevalence rate is compared with previous prevalences studies focusing on Charcot-Marie-Tooth disease or hereditary motor and sensory neurophaty (HMSN). Three patients were classified as the distal spinal muscular atrophy type of CMT and one patient was not possible to classfiy. For seventy-five patients, available to clinical examination within the study, data were collected as to age to onset, symnptoms, clinical findigs and degree of disability.     

Comparative effects of low and high doses of clomipramine and placebo in panic disorder: a double-blind controlled study. French University Antidepressant Group

This study was designed to explore the dose-response relationship for clomipramine in patients with panic disorder, with or without agoraphobia. After 1 week of single-blind placebo pretreatment, 180 such patients were assigned to a multicentre placebo-controlled comparison of the effects of high and low doses of clomipramine, and were followed up for 8 weeks. In alleviating anxiety and panic disorder, both clomipramine doses were more efficacious than placebo for panic disorder and, to a lesser degree, for phobia. The lower dose was better tolerated and at least as effective as the higher dose, sometimes more so. These results indicate the clinically important possibility that low-dose clomipramine is effective and well tolerated.     

Myelography, CT, and MRI of the spinal canal in patients with myelopathy: a prospective study

A prospective study including myelography, CT, and MRI was performed on 36 patients with clinical signs of myelopathy. Evoked potentials and spinal fluid examinations were also carried out. Based on our findings, the patients could be classified as suffering from cryptogenic myelopathy (n = 12), multiple sclerosis (n = 6), spinal stenosis (n = 6), or miscellaneous myelopathies (n = 12). The diameter of the spinal cord was normal in the 2 first groups of patients and of same magnitude evaluated by myelography and CT, while MRI constantly gave higher figures. In only four of the patients important new information was added by CT and MRI (syringomyelia, myelitis, lipomatosis) compared with myelography, although a more precise visualization was often provided. Further diagnostic progress in patients with myelopathy of undetermined etiology may be obtained by including supplementary MRI of the brain disclosing multiple sclerosis in several cases.     

Effect of the 21-aminosteroid U74006F and methylprednisolone on motor function recovery and oedema after spinal cord compression in rats

The effect of the 21-aminosteroid U74006F and methylprednisolone (MP) on motor function and oedema were investigated after spinal cord compression in rats. Each compound was administered i.v. as a single dose 60 min after injury. The hind limb motor function was assessed using the inclined plane technique and expressed as the capacity angle. The water content was calculated as the percent wet weight of the total weight. Prior to compression the capacity angle was close to 62–64°. One day after compression the motor function was reduced significantly in all rats. However, the capacity angle was significantly higher after treatment with U74006F or MP than with vehicle, i.e. 50°± 4, 45°± 5, and 32°± 3, respectively. This improved functional recovery persisted during the initial nine days. After compression of the spinal cord the water content increased to a maximum on day 4 in all groups. The water content was not significantly different in any of the groups except on day one and nine when it was less in groups treated with U74006F. In conclusion, a single i. v. injection of U74006 or MP given 60 min after compression of the spinal cord improved motor function without effecting oedema expressed as water content.     

Development of Neurons and Glial Cells in Cerebral Cortex,Cultured in the Presence or Absence of Bioelectric Activity: Morphological Observations

Chronic blockade of bioelectric activity (BEA) has been shown to increase neuronal cell death in tissue culture, but the effects of this treatment on non-neuronal cells have not been investigated. To determine which cell types are affected by chronic suppression of BEA, we investigated their morphological development in primary cultures of rat cerebral cortex, grown with or without the sodium channel blocker tetrodotoxin (TTX). Morphological development was monitored by phase-contrast microscopy and by immunofluorescent staining of markers specific for neurons (NSE, MAP2, B-50, and the 200 kD neurofilament protein), astrocytes (GFAP), oligodendrocytes (galactocerebroside), macrophages (ED-1) and fibroblasts (fibronectin). Neurons in control cultures steadily increased in size and elaborated a dense network of axons and dendrites during the first 3 weeks. Astrocytes proliferated strongly and formed a 'bottom-layer' on which other cells grew. Part of the astrocytes migrated into the peripheral area of the culture, but retracted to the centre after 14 days in vitro (DIV). Oligodendrocytes and macrophages also increased in number, but oligodendrocytes were completely lost by 28 DIV. After 3 weeks, axons that had grown into the periphery of the culture gradually retracted and/or degenerated, following the retracting astrocytes. Some of the neurons died after 21 DIV, but a large part persisted until 42 DIV. Upon TTX treatment from 5/6 DIV, cultures with few macrophages showed an increase in the proportion of necrotic nuclei at 14 and 21 DIV. The retraction of peripherally located fibres was accelerated by 3 - 4 days and their degeneration was augmented. Neuronal density decreased to zero between 21 and 42 DIV. Astrocytes showed a clear decrease in density from 28 DIV. Conversely, the density of macrophages was increased about two-fold from 14 DIV. These results indicate that both neurons and glia are affected by chronic TTX treatment.     

Cognitive performance in HIV-1 infection: relationship to severity of disease and brain atrophy

We examined cognitive performance in 72 HIV-1 infected patients and 34 controls. None of the patients had opportunistic infections or unusual neoplasms of the central nervous system (CNS). Factors other than HIV-1 known to cause cognitive decline were excluded from both groups. Cognitive functioning analysed with special emphasis on the severity of HIV infection was related to neuroradiological and immunological findings. In patients with AIDS-related complex (CDC IVa) or AIDS (CDC IVc,d), a deterioration of memory as well as cognitive speed and flexibility was detected. Furthermore, memory deficits were associated with central cerebral and infratentorial atrophy in those patients, while no association was found between cognitive deficits and immunological abnormalities. Patients at CDC stages II or III showed slight association between altered cognitive speed and flexibility and elevated leukocyte count, suggesting a subclinical CNS disease already at early stages of HIV infection.     

Dissociated expression of mitochondrial and cytosolic creatine kinases in the human brain: a new perspective on the role of creatine in brain energy metabolism

The phosphocreatine/creatine kinase (PCr/CK) system in the brain is defined by the expression of two CK isozymes: the cytosolic brain-type CK (BCK) and the ubiquitous mitochondrial CK (uMtCK). The system plays an important role in supporting cellular energy metabolism by buffering adenosine triphosphate (ATP) consumption and improving the flux of high-energy phosphoryls around the cell. This system is well defined in muscle tissue, but there have been few detailed studies of this system in the brain, especially in humans. Creatine is known to be important for neurologic function, and its loss from the brain during development can lead to mental retardation. This study provides the first detailed immunohistochemical study of the expression pattern of BCK and uMtCK in the human brain. A strikingly dissociated pattern of expression was found: uMtCK was found to be ubiquitously and exclusively expressed in neuronal populations, whereas BCK was dominantly expressed in astrocytes, with a low and selective expression in neurons. This pattern indicates that the two CK isozymes are not widely coexpressed in the human brain, but rather are selectively expressed depending on the cell type. These results suggest that the brain cells may use only certain properties of the PCr/CK system depending on their energetic requirements.     

Adjustment reactions: a long-term prospective and retrospective follow-up of former patients in a crisis intervention ward

The results of a 5-year follow-up study of 76 patients in a crisis intervention ward who were suffering from an adjustment reaction (brief or prolonged depressive reaction) according to ICD-9 criteria indicate a rather favorable course and outcome using standardized instruments. Only 17% developed a chronic or severe course of primarily depressive symptoms and only 1 (2%) patient committed suicide after discharge, whereas 64% had a very favorable and 18% a favorable course and outcome. This result is reflected in a rather low use of psychiatric and psychotherapeutic outpatient services during the follow-up period.     

Measuring health status in psychiatric community surveys: internal and external validity of the Spanish version of the SF-36

The aims of the present study were to determine the acceptability of the Spanish version of the Short Form (SF-36) health survey questionnaire for its use in mental health research on the general population, and to evaluate its internal and external validity, using data obtained from a representative community sample of 1250 adults of working age. The internal consistency of the different dimensions of the questionnaire was high. Concurrent validity was tested by examining its correlation with the 12-item General Health Questionnaire (GHQ-12). Construct validity was determined by studying the extent to which scores on different variables reflected the expected distribution of health status for and between certain groups. Our findings provide strong evidence for the acceptability and validity of the SF-36 when used as part of a community mental health survey.     

CSF follow-up in HIV-1 infection: intrathecal production of HIV-specific and unspecific IGG, and beta-2-microglobulin increase with duration of HIV-1 infection

Ninety-nine sequential cerebrospinal fluid (CSF) samples from 28 human imunodeficiency virus-1 (HIV-1)-infected patients were analyzed during the follow-up of 9 months to 4 years. Intrathecal synthesis of HIV-antibodies and IgG (p<0.01), and the levels of beta-2-microglobulin (β2m) in the CSF (p<0.05) and serum (p<0.01) increased with duration of HIV-1 infection. No effect of duration of HIV-1 infection was observed on the individual CSF white cell counts and the levels of blood-brain-barrier (BBB) permeability. In 13 patients with HIV-1-associated central nervous system (CNS) disease, the effect of duration was seen as an increase of the individual β2m levels in serum (p<0.01). Moreover, 7 of 9 patients who developed neurological disease or showed its progression during the study increased the level of β2m in the CSF. All of them increased the level of β2m in serum. In 15 neurologically healthy subjects, the effect of duration was expressed as an increase of the level of individual β2m in CSF (p<0.05) and intrathecal IgG synthesis (p<0.01). In the AIDS group, the level of β2m in the CSF increased, but in less severe stages the dependency of the individual CSF parameters on disease duration was not found. Our results indicate that elevated levels of β2m in CSF and serum appear to predict progression of neurological and systemic diseases, respectively. Elevated β2m in the CSF of clinically intact individuals may indicate subclinical neurological disease caused by HIV-1. Serial monitoring of other majro immunological parameters is less informative because of a marked variability and an inability to predict disease progression.     

Prior poliomyelitis: an immunohistochemical study of cytoskeletal proteins and a marker for muscle fibre regeneration in relation to usage of remaining motor units

Patients with prior poliomyelitis with paresis and excessive use (n = 8) and low use (n = 6) of residual anterior tibial motor units (MUs) during walking were subjected to muscle biopsy of the anterior tibial muscle (TA). Antibodies directed against cytoskeletal proteins, spectrin and desmin, and against Leu-19, a myoblast and satellite cell related antigen, were applied. In the patients with excessive use of residual MUs there was an almost total predominance of hypertrophic type I fibres. In the hypertrophic fibres, staining for spectrin and desmin was normal while staining for Leu-19 was seen in a few fibres. Scattered atrophic fibres seen in the patients with excessive use showed staining for spectrin, desmin and Leu-19. In the patients with low use of residual MUs there were extensive pathological muscle fibre changes. Increased staining for spectrin, desmin and Leu-19 was found in most of the atrophic fibres. The predominance of type I fibres in the patients with excessive use of residual MUs is suggested to be due to muscle fibre transformation. The normal staining pattern for spectrin and desmin in the hypertrophic fibres indicates a normal cytoskeletal structure which might suggest that the adaptive muscle fibre changes are adequate to meet the increased demand. The increased staining for spectrin, desmin and Leu-19 in the atrophic fibres might indicate an ongoing denervation process which earlier has been suggested as an important factor for the development of postpolio progressive muscular atrophy.     

GABA-activated Chloride Currents of Postnatal Mouse Retinal Ganglion Cells are Blocked by Acetylcholine and Acetylcarnitine: How Specific are Ion Channels in Immature Neurons?

The goal of this study was to clarify pharmacological properties of GABA_A receptors in cells of the mouse retinal ganglion cell layer in situ. Spontaneous synaptic currents and responses to exogenous GABA were recorded from individual neurons in retinal whole mounts (postnatal days 1–3) or retinal stripe preparations (postnatal days 4–6). Drugs were applied by a fast local superfusion system. Current responses were measured with the patch-clamp technique in the whole-cell configuration. All cells responded to exogenous GABA (average EC₅₀ and Hill coefficient: 16.7 μM and 0.95 respectively) and generated GABAergic synaptic currents in response to elevated KCI. GABA-induced currents of retinal ganglion cells were blocked by bicuculline, picrotoxin and Zn²⁺, as well as strychnine, and increased by pentobarbital, clonazepam and 3α-hydroxy-5α-pregnan-20-one. In some retinal ganglion cells GABA caused an increase in the frequency of spontaneous synaptic currents, which points to a partially depolarizing action of this traditionally inhibitory neurotransmitter in the neural retina. Our major observation is that acetylcholine and acetylcarnitine blocked or reduced GABAergic inhibitory postsynaptic currents and responses to exogenous GABA. This effect was seen in only a fraction of retinal ganglion cells and occurred in both the undesensitized and the desensitized state of the GABA_A receptor. The block was voltage-independent and persisted during coapplication with the nicotinic and muscarinic acetylcholine receptor antagonists D-tubocurarine and atropine. In contrast to GABA-activated Cl⁻ currents, glycine-activated Ch currents remained unaffected by acetylcholine and acetylcarnitine. Acetylcarnitine had no effect on voltage-activated Ca²⁺ channel currents and glutamate-activated currents. Similar results were obtained in a dissociated cell culture preparation from the neonatal rat superior colliculus. In these cells acetylcholine induced a rightward shift in the dose - response curve for GABA. Taken together, these results indicate that acetylcholine and acetylcarnitine can act directly at the GABA_A binding site and thereby reduce the action of GABA in the immature retina.     

Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-l-carnitine

Treatment of rats with i.c.v. injected streptozotocin (STREP) may provide a relevant model of neurodegeneration that is induced by a decrease in the central metabolism of glucose. Acetyl-l-carnitine (ALCAR) enhances the utilization of alternative energy sources and by such a mechanism of action ALCAR could antagonize the effects of STREP treatment. In this study the effects of chronic treatment with ALCAR were evaluated on spatial discrimination learning in the Morris task and choline acetyltransferase (ChAT) activity of middle-aged STREP-treated rats. Chronic treatment with ALCAR attenuated both the STREP-induced impairment in spatial bias and the decrease in hippocampal ChAT activity. These findings indicate that ALCAR treatment has a neuroprotective effect, although further studies are needed to characterize the mechanism of action of ALCAR in this model.     

Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-l-carnitine

Treatment of rats with i.c.v. injected streptozotocin (STREP) may provide a relevant model of neurodegeneration that is induced by a decrease in the central metabolism of glucose. Acetyl-l-carnitine (ALCAR) enhances the utilization of alternative energy sources and by such a mechanism of action ALCAR could antagonize the effects of STREP treatment. In this study the effects of chronic treatment with ALCAR were evaluated on spatial discrimination learning in the Morris task and choline acetyltransferase (ChAT) activity of middle-aged STREP-treated rats. Chronic treatment with ALCAR attenuated both the STREP-induced impairment in spatial bias and the decrease in hippocampal ChAT activity. These findings indicate that ALCAR treatment has a neuroprotective effect, although further studies are needed to characterize the mechanism of action of ALCAR in this model.