Quantitative analysis of activated microglia, ramified and damage of processes in the frontal and temporal lobes of chronic schizophrenics

Under pathological conditions, microglial cells undergo activation, which is manifested by the expression of histocompatibility locus antigens class II (HLA II) on their surface as well as by proliferation and varied morphological forms. In schizophrenia, characterised by an essential role played by immunological mechanisms, quantitative analysis of activated microglia -- with well-developed ramification (RM), degenerative traits and damaged processes (from their shortening to their complete lack) (DM) -- may contribute to better understanding of schizophrenia etiopathogenesis. Quantitative analysis was performed on slices derived from the frontal and temporal lobes of 9 brains of schizophrenics and 6 control brains. The nonparametric Mann-Whitney U test was used to assess quantitative differences in the distribution of microglia in these regions of the brain. Statistical analyses were performed with STATISTICA 6.5 Programme. In both structures of the brain, the number of activated microglial cells was higher in schizophrenic brains than in control brains. Except for the first layer of the cerebral cortex with the same amounts of RM and DM, the number of DM cells in the remaining regions was several-fold higher than that of RM cells. It is most likely that disturbances in calcium metabolism and energetic balance as well as antibodies produced in the course of schizophrenia are the agents able to trigger a cascade transforming RM into DM. Quantitative differences in RM and DM, observed between the studied structures and cortical regions, could depend not only on functioning of inter-neuronal and inter-structural links. Our study suggests a pivotal role of microglial cells in repair processes and/or etiopathogenesis of schizophrenia and indicates that they undergo substantial damage in the course of chronic schizophrenia.     

Increase in HLA-DR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics

Glia play a major role in neuronal migration, synapse formation, and control of neurotransmission in the developing and mature nervous system. This study investigated whether chronic schizophrenia is associated with glial changes in 3 regions of the cerebral cortex: dorsolateral prefrontal cortex (Brodmann's area 9), the superior temporal gyrus (area 22), and the anterior cingulate gyrus (area 24). In a blind study, astroglia and microglia were identified immunocytochemically in frozen sections from postmortem schizophrenic and control brains. Astroglia and microglia were identified using antibodies to glial fibrillary acidic protein (GFAP) and class II human leucocyte antigen (HLA-DR) respectively. They were then quantified for each cortical layer. Significant differences were found in HLA-DR+ microglial numerical density in 2 of the areas. A 28% increase (p < 0.05) was found in area 9 in 8 schizophrenics (115 +/- 9 cells/mm2) compared with 10 controls (89 +/- 5 cells/mm2), when combining all cortical layers and both cerebral hemispheres. For area 22, there was a 57% increase (p < 0.01) in microglia in 7 schizophrenics (139 +/- 6 cells/mm2) compared with 10 controls (88 +/- 5 cells/mm2). In area 24 the same trend was evident, but the results did not reach significance. Microglial number was further analyzed for each cortical layer, which confirmed the overall pattern. For all areas, numerical density of astroglia showed no significant differences between schizophrenics and controls. Cortical thickness was measured in all areas and total neuronal numerical density was estimated for area 22. Again, no significant differences were found between schizophrenics and controls. This study demonstrates a specific increase in the numerical density of HLA-DR+ microglia in temporal and frontal cortex of chronic schizophrenics, not related to aging, which might be implicated in possible changes in cortical neuropil architecture in schizophrenia.     

Monoaminergic innervation of the frontal and temporal lobes in Alzheimer's disease

Seven markers of ascending (corticopetal) dopaminergic, noradrenergic and serotonergic neurones and choline acetyltransferase activity have been studied postmortem in frontal and temporal cortex from subjects with Alzheimer's disease and compared with a matched group of controls. Dopaminergic neurones (concentrations of dopamine, dihydroxyphenylacetic acid and homovanillic acid) were not deficient but some markers of the other neurones were affected. Noradrenaline and serotonin concentrations were reduced whereas the concentrations of their metabolites were either unaltered (5-hydroxyindoleacetic acid) or increased (3-methoxy-4-hydroxyphenylglycol). All deficits were most pronounced in the temporal cortex. Severely demented subjects had evidence of generalized neuronal loss, whereas those with moderate dementia showed significant loss of only choline acetyltransferase activity. In Alzheimer subjects, a significant relationship (inverse) was found between 5-hydroxyindoleacetic acid concentration and the number of neurofibrillary tangles.     

The frontal lobes, basal ganglia, and temporal lobes as sites for schizophrenia

Positron emission tomography studies with fluorodeoxyglucose in patients with schizophrenia are reviewed and findings in the frontal lobes, basal ganglia, and temporal lobes summarized from more than 20 published studies. Despite methodological and clinical population differences between studies, most reports indicate that patients with schizophrenia are more likely to be low in these areas than in the occipital lobe, cerebellum, or in white matter. This is consistent with blood flow and some neuroanatomical findings. Cluster analysis on our own sample suggests that patients may be low in all three areas rather than a pattern of three distinct clusters. Further study of individual symptom differences, medication effects, and of psychophysical tasks salient for these brain areas is indicated.     

The representation of information about faces in the temporal and frontal lobes

Neurophysiological evidence is described showing that some neurons in the macaque inferior temporal visual cortex have responses that are invariant with respect to the position, size and view of faces and objects, and that these neurons show rapid processing and rapid learning. Which face or object is present is encoded using a distributed representation in which each neuron conveys independent information in its firing rate, with little information evident in the relative time of firing of different neurons. This ensemble encoding has the advantages of maximising the information in the representation useful for discrimination between stimuli using a simple weighted sum of the neuronal firing by the receiving neurons, generalisation and graceful degradation. These invariant representations are ideally suited to provide the inputs to brain regions such as the orbitofrontal cortex and amygdala that learn the reinforcement associations of an individual's face, for then the learning, and the appropriate social and emotional responses, generalise to other views of the same face. A theory is described of how such invariant representations may be produced in a hierarchically organised set of visual cortical areas with convergent connectivity. The theory proposes that neurons in these visual areas use a modified Hebb synaptic modification rule with a short-term memory trace to capture whatever can be captured at each stage that is invariant about objects as the objects change in retinal view, position, size and rotation. Another population of neurons in the cortex in the superior temporal sulcus encodes other aspects of faces such as face expression, eye gaze, face view and whether the head is moving. These neurons thus provide important additional inputs to parts of the brain such as the orbitofrontal cortex and amygdala that are involved in social communication and emotional behaviour. Outputs of these systems reach the amygdala, in which face-selective neurons are found, and also the orbitofrontal cortex, in which some neurons are tuned to face identity and others to face expression. In humans, activation of the orbitofrontal cortex is found when a change of face expression acts as a social signal that behaviour should change; and damage to the orbitofrontal cortex can impair face and voice expression identification, and also the reversal of emotional behaviour that normally occurs when reinforcers are reversed.     

Reduced communication between frontal and temporal lobes during talking in schizophrenia.

BACKGROUND: Communication between the frontal lobes, where speech and verbal thoughts are generated, and the temporal lobes, where they are perceived, may occur through the action of a corollary discharge. Its dysfunction may underlie failure to recognize inner speech as self-generated and account for auditory hallucinations in schizophrenia. METHODS: Electroencephalogram was recorded from 10 healthy adults and 12 patients with schizophrenia (DSM-IV) in two conditions: talking aloud and listening to their own played-back speech. Event-related electroencephalogram coherence to acoustic stimuli presented during both conditions was calculated between frontal and temporal pairs, for delta, theta, alpha, beta, and gamma frequency bands. RESULTS: Talking produced greater coherence than listening between frontal-temporal regions in all frequency bands; however, in the lower frequencies (delta and theta), there were significant interactions of group and condition. This finding revealed that patients failed to show an increase in coherence during talking, especially over the speech production and speech reception areas of the left hemisphere, and especially in patients prone to hallucinate. CONCLUSIONS: Reduced fronto-temporal functional connectivity may contribute to the misattribution of inner thoughts to external voices in schizophrenia.     

The role of frontal and temporal lobes in visual discrimination task--depth ERP studies.

Visual event-related potentials were simultaneously recorded from different anatomical structures within frontal and temporal lobes in 12 epileptic patients. A simple discrimination task was performed to complement previous studies on the localization of P3 generators in the human brain. The role of multiple cortical structures in the generation of both P3a and P3b components was confirmed. Activities contemporary to a visual P3b were recorded in the hippocampus, amygdala and temporal pole. Anterior cingulate and orbitofrontal cortices-generated activities more closely related in time to the surface P3a. Earlier events related to visual discrimination took place in more lateral sites of the frontal lobe, but their contribution to the scalp P3 remains uncertain. Subsequently, mutual temporal relations among single generators were analyzed. The results suggested a processing-level hierarchy within the neural network for directed attention with a key role played by the dorsolateral prefrontal cortex.     

Electrophysiologic investigation of the anterior temporal and frontal lobes: sphenoidal and intraorbital electrodes

The authors have evaluated the interest of sphenoidal electrodes in detection of internal temporal spikes, and intra-orbital electrodes in the detection of orbito-frontal spikes. From a study of 26 patients, 21 with sphenoidal electrodes, 3 with intra-orbital electrodes and 2 with both electrodes, they observed the sensitivity and specificity of such electrodes in detecting spikes with no traduction upon extra-cranial electrodes, or with an unsuspected traduction as spikes at a distance from deep electrodes, or spikes on 2 foci, or bisynchronous discharges. Sphenoidal and intra-oribital electrodes constitute a non-invasive method that provides excellent information in the exploration of the mesiobasal cerebral face. Indications for the use of such a method are complex absences without EEG traduction or with an unsuspected traduction and without abnormalities on CT scan, in the context of functional surgery of epilepsy.     

Role of the frontal lobes in the propagation of mesial temporal lobe seizures.

The depth ictal electroencephalographic (EEG) propagation sequence accompanying 78 complex partial seizures of mesial temporal origin was reviewed in 24 patients (15 from the University of Pittsburgh Epilepsy Center and 9 from UCLA). All patients were monitored with bilateral mesial frontal and mesial temporal depth electrodes and later received anterior temporal lobectomy. Ictal EEG records were categorized according to sequence of spread from the temporal focus to the other regions. Although propagation patterns varied both within and between patients, certain features were notable: (a) It was very common for seizure activity to spread initially to the ipsilateral frontal lobe (observed in 22 of 24 patients). (b) The most common mode of spread (15 of 24 patients) was initiating temporal lobe----ipsilateral frontal lobe----contralateral frontal lobe----contralateral temporal lobe. (c) Occasionally, seizure discharges invaded the frontal lobes but failed to invade the contralateral temporal lobe (2 of 24 patients). (d) Seizure activity occasionally invaded the contralateral temporal lobe prior to invading the frontal lobes (2 of 24 patients). Other notable features included (i) a clear tendency for mesial temporal seizure discharges initially to invade orbitofrontal (as opposed to anterior cingulate) cortex and (ii) the emergence of a period of clear asymmetry in the frontal lobes during which high-amplitude, rapid discharges were present on the side ipsilateral to the initiating temporal lobe. These results suggest that the prefrontal region, especially the orbitofrontal cortex, is strongly influenced by mesial temporal ictal activity. This region appears to be frequently involved in the propagation of seizures initiated in the mesial temporal lobe and may play a role in the interhemispheric propagation of mesial temporal seizures.     

Epilepsy and the frontal lobes

Although the frontal lobes contain a large proportion of the total cerebral cortex in human brain, the epilepsies arising in this region are less studied and less well characterised than epilepsies arising in the mesial temporal lobe. Detailed studies of seizure semiology have identified a number of patterns of frontal lobe seizure, but with inconsistency across studies, and with limited evidence that specific patterns arise in specific discrete frontal lobe regions. In contrast to mesial temporal lobe epilepsy, there is no consistent pattern of cognitive impairment seen in patients with frontal lobe epilepsy, although some evidence exists to support the notion that cognitive function may be impaired. Given the rich interconnectivity between frontal lobes and many other brain regions, it is not surprising to find functional deficits in the frontal lobes in patients with epilepsy arising in other sites; this is best studied in patients with temporal lobe epilepsy. Current concepts in epilepsy suggest that epilepsies hitherto regarded as idiopathic generalised (rather than focal) may in fact have a focal origin of seizure activity; this may be supported by increasing evidence for focal structural and functional frontal lobe abnormalities in idiopathic generalised epilepsies.     

Disruption of inhibitory control of memory following lesions to the frontal and temporal lobes

A group of patients with lesions to the frontal lobes, a group with lesions to the temporal lobes, and groups of non-brain damaged controls took part in three experiments. The first experiment used directed forgetting (DF) by items, the second DF by lists, and the third retrieval induced forgetting (RIF). Frontal patients with right side lesions could not intentionally inhibit but all frontal patients showed normal RIF. Temporal patients with left side lesions had abnormal DF by lists and all the temporal patients had abnormal RIF. These findings are explained in terms of impairment to executive thought avoidance control processes in frontal patients and impaired knowledge access to long-term memory in temporal patients.     

Decreased energy demanding processes in the frontal lobes of schizophrenics due to neuroleptics? A P-magneto-resonance spectroscopic study

In the present investigation on ³¹P-magneto-resonance spectroscopic parameters in the frontal lobe, we found phosphocreatine levels and the ratio phosphocreatine/adenosine triphosphate to be increased (12.62±1.98% resp. 0.31±0.06) in 50 neuroleptic-treated schizophrenics, whereas no differences were detected in 10 neuroleptic-free patients (11.66±2.57% resp. 0.29±0.08) compared to 36 controls (11.37±1.45 resp. 0.29±0.04). This result points to a major role of neuroleptics in the metabolism of high-energy phosphates.     

Selectively distributed processing of visual object recognition in the temporal and frontal lobes of the human brain

Evoked potentials to visually driven cognitive tasks were recorded through depth electrodes placed bilaterally within the amygdala, hippocampus, midtemporal and inferotemporal cortex, and lateral frontal cortex of 6 epileptic patients. Task-related differential response patterns were used to identify the recording sites engaged by specific aspects of visual encoding. In this group of 6 patients, the amygdala was most frequently engaged in encoding the familiarity of faces; midtemporal and inferotemporal cortex, in encoding perceptual identity and object categorization; and lateral frontal cortex, in holding visual object information in working memory. The two aspects of encoding that most frequently engaged the hippocampal region were related to working memory and object categorization. The processing of complex visual knowledge is thus anatomically distributed but regionally specialized. These experiments also showed that identical input and output parameters can engage different areas of the brain depending on the nature of the instructional set.     

Absence of activation in frontal structures during psychological testing of chronic schizophrenics.

The distribution of activity in the dominant hemisphere was measured with the regional cerebral blood flow (rCBF) technique in 27 chronic schizophrenics and 15 non-schizophrenic control subjects (alcoholics) at rest and during phychological testing. In the non-schizophrenics, an increase of rCBF was observed during the test in frontal regions. In the chronic schizophrenics, on the other hand, no or only a very limited increase was recorded. In postcentral structures the flow response during the testing was, by and large, equal in the psychotics and the controls. The findings support the hypothesis advanced previously by the authors that in chronic schizophrenia there is defective transmission in the mediothalamic frontocortical projection bundle. This defect also appears responsible for the abnormally low resting flow (activity) in the dominant hemisphere in chronic schizophrenia which we have described previously.