Magnetic resonance imaging of mediodorsal, pulvinar, and centromedian nuclei of the thalamus in patients with schizophrenia

BACKGROUND: Postmortem and magnetic resonance imaging (MRI) data have suggested volume reductions in the mediodorsal (MDN) and pulvinar nuclei (PUL) of the thalamus. The centromedian nucleus (CMN), important in attention and arousal, has not been previously studied with MRI. METHODS: A sample of 41 patients with schizophrenia (32 men and 9 women) and 60 healthy volunteers (45 men and 15 women) underwent assessment with high-resolution 1.2-mm thick anatomical MRI. Images were differentiated to enhance the edges and outline of the whole thalamus, and the MDN, PUL, and CMN were outlined on all slices by a tracer masked to diagnostic status. RESULTS: Significantly smaller volumes of the MDN and PUL were found in patients with schizophrenia compared with controls. Volume relative to brain size was reduced in all 3 nuclei; differences in relative reduction did not differ among the nuclei. The remainder of the thalamic volume (whole thalamus minus the volume of the 3 delineated nuclei) was not different between schizophrenic patients and controls, indicating that the volume reduction was specific to these nuclei. Volume relative to brain size was reduced in all 3 nuclei and remained significant when only patients who had never been exposed to neuroleptic medication (n = 15) were considered. For the MDN, women had larger relative volumes than men among controls, but men had larger volumes than women among schizophrenic patients. CONCLUSIONS: Three association regions of the thalamus that have reciprocal connectivity to schizophrenia-associated regions of the cortex have significantly smaller volumes on MRI in patients with schizophrenia.     

Abnormal glucose metabolism in the mediodorsal nucleus of the thalamus in schizophrenia

OBJECTIVE: Three thalamic nuclei--the mediodorsal nucleus, pulvinar, and centromedian nucleus--each have unique reciprocal circuitry with cortical and subcortical areas known to be affected in schizophrenia. To determine if the disorder is also associated with dysfunction in the mediodorsal nucleus, pulvinar, and centromedian nucleus, relative glucose metabolism in these regions was measured in a large group of unmedicated patients with schizophrenia. METHOD: [18F]-deoxyglucose positron emission tomography (PET) and matching T1-weighted magnetic resonance imaging (MRI) scans were obtained for 41 unmedicated patients with schizophrenia and 60 age- and sex-matched healthy subjects. The PET and MRI images for each subject were coregistered, and the whole thalamus, mediodorsal nucleus, pulvinar, and centromedian nucleus were traced on the MRI image. Relative glucose metabolism in these regions was assessed. RESULTS: Patients with schizophrenia showed significantly lower relative glucose metabolism in the mediodorsal nucleus and the centromedian nucleus and significantly higher relative glucose metabolism in the pulvinar, compared with the healthy subjects. Lower relative glucose metabolism in the total thalamus, mediodorsal nucleus, and pulvinar was associated with greater overall clinical symptoms as measured by the Brief Psychiatric Rating Scale. Lower relative glucose metabolism in the pulvinar was associated with more hallucinations and more positive symptoms, while lower relative glucose metabolism in the mediodorsal nucleus was associated with more negative symptoms. CONCLUSIONS: The findings suggest that patients with schizophrenia exhibit dysfunction in thalamic subdivisions with distinct cortical connections and that these thalamic subdivisions have specific associations with clinical symptoms.     

Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder

BACKGROUND: The importance of neuronal interactions in development, the cortical dependence of many thalamic nuclei, and the phenomenon of transsynaptic degeneration suggest possible abnormalities in thalamic nuclei with connections to other brain regions implicated in schizophrenia. Because frontal and temporal lobe volumes are diminished in schizophrenia, volume loss could characterize their primary thalamic relay nuclei (mediodorsal nucleus [MDN] and pulvinar). METHODS: Tracers delineated the thalamus, MDN, and pulvinar on contiguous 1.2-mm magnetic resonance images in 12 schizophrenic patients, 12 with schizotypal personality disorder (SPD), and 12 normal control subjects. The MDN and pulvinar were rendered visible by means of a Sobel intensity-gradient filter. RESULTS: Pixel overlap for delineation of all structures by independent tracers was at least 80%; intraclass correlations were r = 0.78 for MDN and r = 0.83 for pulvinar. Pulvinar volume was smaller in schizophrenic (1.22 +/- 0.24 cm(3)) and SPD (1.20 +/- 0.23 cm(3)) patients than controls (1.37 +/- 0.25 cm(3)). Differences for MDN were not statistically significant; however, when expressed as percentage of total brain volume, pulvinar and MDN together were reduced in SPD (0.14%) and schizophrenic (0.15%) patients vs controls (0.16%). Reductions were more prominent in the left hemisphere, with MDN reduced only in the schizophrenic group, and pulvinar in both patient groups. Total thalamic volume did not differ among the 3 groups. CONCLUSIONS: Measurement of MDN and pulvinar in magnetic resonance images is feasible and reproducible. Schizophrenic and SPD patients have volume reduction in the pulvinar, but only schizophrenic patients show reduction relative to brain volume in MDN.     

Three-dimensional analysis with MRI and PET of the size, shape, and function of the thalamus in the schizophrenia spectrum.

OBJECTIVE: In an exploration of the schizophrenia spectrum, the authors compared thalamic size, shape, and metabolic activity in unmedicated patients with schizophrenia and schizotypal personality disorder to findings in age- and sex-matched healthy control subjects. METHOD: Coregistered magnetic resonance imaging (MRI) and positron emission tomography scans were obtained in 27 schizophrenic patients, 13 patients with schizotypal personality disorder, and 32 control subjects who performed a serial verbal learning test during tracer uptake. After thalamus edges were outlined on 1.2-mm MRI scans, a radial warping program yielded significance probability mapping in three dimensions. RESULTS: Significance probability mapping (with resampling) identified an area in the region of the mediodorsal nucleus bilaterally with significantly lower relative metabolism in the schizophrenia group than in either the control or schizotypal personality disorder groups, which did not differ from each other. The three groups did not differ significantly in total thalamic volume in square millimeters or thalamic volume relative to brain volume. Shape analyses revealed that schizophrenic patients had significantly fewer pixels in the left anterior region, whereas patients with schizotypal personality disorder had significantly fewer pixels in the region of the right mediodorsal nucleus than did control subjects. CONCLUSIONS: Schizophrenic patients showed significant metabolism and shape differences from control subjects in selective subregions of the thalamus, whereas patients with schizotypal personality disorder showed only a difference in shape. Because the mediodorsal and anterior nuclei have different connections with limbic and prefrontal structures, the anterior thalamic shrinkage and mediodorsal metabolic and shape changes might relate to the different clinical pictures in schizotypal personality disorder and schizophrenia.     

Stereologic analysis of the lateral geniculate nucleus of the thalamus in normal and schizophrenic subjects

Reduction of volume and neuronal number has been found in several association nuclei of the thalamus in schizophrenic subjects. Recent evidence suggests that schizophrenic patients exhibit abnormalities in early visual processing and that many of the observed perceptual deficits are consistent with dysfunction of the magnocellular pathway, i.e. the visual relay from peripheral retinal cells to the two ventrally located magnocellular layers of the lateral geniculate nucleus (LGN). The present study was undertaken to determine whether abnormalities in cell number and volume of the LGN are associated with schizophrenia and whether the structural alterations are restricted to either the magnocellular or parvocellular subdivisions of the LGN. Series of Nissl-stained sections spanning the LGN were obtained from 15 schizophrenic and 15 normal control subjects. The optical disector/fractionator sampling method was used to estimate total neuronal number, total glial number and volume of the magnocellular and parvocellular subdivisions of the LGN. Cell number and volume of the LGN in schizophrenic subjects were not abnormal. Volume of both parvocellular and magnocellular layers of the LGN decreased with age. These findings do not support the hypothesis that early visual processing deficits in schizophrenic subjects are due to reduction of neuronal number in the LGN.     

Thalamic volumes in patients with first-episode schizophrenia

OBJECTIVE: The thalamus, a highly evolved sensory and motor gateway to the cortex, has been implicated in the pathophysiology of several illnesses, including schizophrenia. Several studies have suggested thalamic volume differences in patients with schizophrenia, although only a few studies have examined thalamic structure in new-onset patients. METHOD: The authors used magnetic resonance imaging to measure thalamic volumes in previously untreated patients with first-episode schizophrenia (N=16) relative to those of healthy comparison subjects (N=25). The age range of the patients and comparison subjects was 15 to 45 years of age. Thalamic volumes in the right and left hemispheres were segmented and analyzed, both separately and as total thalamic volume, by a rater blind to clinical data. The thalamus was further segmented into regions that roughly reflected individual thalamic nuclei. Analysis of covariance was used to control for intracranial volume. RESULTS: Right, left, and total thalamic volumes of the patients with schizophrenia were significantly smaller than those of the comparison subjects. Significantly smaller volumes were found in the left central medial subdivision of the patients as well as a smaller volume in the right central medial subdivision that approached significance. These regions primarily comprised the dorsomedial nucleus, a thalamic nucleus thought to be an important component of aberrant circuitry in schizophrenia. Significant volume differences were also seen in the left anterior, right anterior, and right posterior medial subdivisions. CONCLUSIONS: These findings suggest significant thalamic volumetric differences between patients with newly diagnosed schizophrenia and healthy comparison subjects. Future analysis of individual thalamic nuclei may reveal important, specific relationships between thalamic abnormalities and schizophrenia.     

Low medial and lateral right pulvinar volumes in schizophrenia: a postmortem study

OBJECTIVE: In this study, the volume and neuronal number of the pulvinar thalamic nucleus in schizophrenia patients were measured. METHOD: The authors examined medial and lateral pulvinar nuclei bilaterally in 27 patients with schizophrenia and 28 normal comparison subjects. RESULTS: In the comparison subjects, the medial pulvinar was larger on the right. The right but not left pulvinar nuclei were smaller in the schizophrenia patients than in the comparison subjects. The number of neurons showed similar trends. CONCLUSIONS: These findings confirm low pulvinar volume in schizophrenia and show that it affects both medial and lateral nuclei. The lateralized findings may reflect pulvinar connections with asymmetrical neocortical regions and their asymmetrical involvement in schizophrenia.     

Abnormalities of thalamic activation and cognition in schizophrenia

OBJECTIVE: Functional and structural magnetic resonance imaging (MRI) was used to investigate relationships among structure, functional activation, and cognitive deficits related to the thalamus in individuals with schizophrenia and healthy comparison subjects. METHOD: Thirty-six schizophrenia subjects and 28 healthy comparison subjects matched by age, gender, race, and parental socioeconomic status underwent structural and functional MRI while performing a series of memory tasks, including an N-back task (working memory), intentional memorization of a series of pictures or words (episodic encoding), and a yes/no recognition task. Functional activation magnitudes in seven regions of interest within the thalamic complex, as defined by anatomical and functional criteria, were computed for each group. RESULTS: Participants with schizophrenia exhibited decreased activation within the whole thalamus, the anterior nuclei, and the medial dorsal nucleus. These nuclei overlap with subregions of the thalamic surface that the authors previously reported to exhibit morphological abnormalities in schizophrenia. However, there were no significant correlations between specific dimensions of thalamic shape variation (i.e., eigenvectors) and the activation patterns within thalamic regions of interest. Better performance on the working memory task among individuals with schizophrenia was significantly associated with increased activation in the anterior nuclei, the centromedian nucleus, the pulvinar, and the ventrolateral nuclei. CONCLUSIONS: These results suggest that there are limited relationships between morphological and functional abnormalities of the thalamus in schizophrenia subjects and highlight the importance of investigating relationships between brain structure and function.     

Caudate size in first-episode neuroleptic-naive schizophrenic patients measured using an artificial neural network.

BACKGROUND: Structural brain imaging studies have demonstrated an increase in caudate volume in schizophrenic patients medicated with typical neuroleptics and a volume decrease following treatment with atypical neuroleptics. The measurement of striatal volume in patients who have never been treated with neuroleptics may indicate whether these changes are superimposed on intrinsic basal ganglia pathology in schizophrenia or are solely neuroleptic-induced. METHODS: We studied 36 first-episode, neuroleptic-naive schizophrenic patients and 43 control subjects using an artificial neural network (ANN) to identify and measure the caudate nucleus. The resulting volumes were analyzed using an ANCOVA controlling for intracranial volume, age, gender, and socioeconomic status. RESULTS: The mean volume difference between the caudate nuclei of patients and control subjects was .297 mL, the caudate nuclei of the patients being smaller than those of controls. When we covaried for intracranial volume, this was a statistically significant difference in caudate volume (n = 79; df = 1,75; F = 4.18; p > .04). CONCLUSIONS: Caudate nuclei of neuroleptic naive schizophrenic patients are significantly smaller than those of controls. This suggests that patients suffering from schizophrenia may have intrinsic pathology of the caudate nucleus, in addition to the pathology observed as a consequence of chronic neuroleptic treatment.     

Transient fetal structure,the gangliothalamic body,connects telencephalic germinal zone with all thalamic regions in the developing human brain

Previous studies reported that telencephalic proliferative zones contribute to the development of the pulvinar thalamic nucleus in the human brain (Rakić and Sidman [1969] Z. Anat. Entwicklungsgesch. 129:53–82). The present study examined their possible contribution to the development of other thalamic nuclei. Postmortem brain tissue from human fetuses ranging between 10.5 and 40 weeks of gestation (wg) was processed by Nissl staining, Golgi impregnation, and MAP2 (microtubule-associated protein 2) immunocytochemistry. The gangliothalamic body, suggested to serve as a conduit for cells migrating from the ganglionic eminence to the thalamus, was found in the period from 15 to 34 wg in all rostrocaudal thalamic regions, particularly at the level of the anterior nuclear complex, mediodorsal and pulvinar nucleus, and in addition, the lateral geniculate nucleus. In Nissl-stained sections, the gangliothalamic body is a thin cellular layer situated beneath the thalamic surface, near the telencephalo-diencephalic junction. In Golgi- and MAP2-stained sections, it is a stream of mostly bipolar cells extending from the ganglionic eminence to the medial thalamus. In addition, MAP2-immunoreactivity confirms the neuronal nature of its cells. The present study further supports the hypothesis that certain neurons migrate from the ganglionic eminence to the thalamus through the transient gangliothalamic body during fetal development. Moreover, our data indicate that both the association (mediodorsal and pulvinar), as well as the anterior (limbic) and specific relay nuclei are potential recipients of the telencephalic neurons. J. Comp. Neurol. 384:373–395, 1997. © 1997 Wiley-Liss, Inc.     

Pathology of the thalamus and schizophrenia--an overview

Since the beginning of the 20 (th) century, the thalamus was regarded as a brain region which may be involved in the pathogenesis of schizophrenia. Distinct thalamic nuclei were morphologically analyzed with qualitative methods with an emphasis on the mediodorsal nucleus. However, the reported results were inconsistent. After the introduction of quantitative neuroanatomical methods, it became obvious that the volume and cell reductions are not only present in the association nuclei, but also in the limbic (N. anteroventralis) and motor thalamic nuclei (N. ventrolateralis posterior). The involvement of distinct thalamic nuclei is supported by structural MRI studies which have shown a moderate but significant volume reduction of the whole thalamus in this disease. The majority of fMRI and PET studies reported a reduction of the metabolic activity or blood flow in the thalamus in patients with schizophrenia. The similarity between the structural changes in animal models of thalamic plasticity and the structural thalamic alterations in schizophrenia suggest an involvement of neuroplasticity mechanisms in the pathogenesis of these alterations. Post-mortem studies and In-vivo receptor studies suggest altered glutamatergic, dopaminergic and membrane-associated mechanisms within thalamic pathology in schizophrenia. On the psychopathological level, there is a similarity between some of the psychic manifestations of thalamic lesions and symptoms of the schizophrenic disease. There are also reports on volume reduction of the whole thalamus in first-episode neuroleptic-free patients. It appears unlikely that the neuroleptic medication plays an etiological important role, since no significant correlations were found between the volume and cell reductions and the neuroleptic treatment period. The reviewed data suggest that distinct thalamic nuclei and therefore distinct neuronal circuits are involved in the pathogenesis of schizophrenia.     

Functional connectivity between the thalamus and visual cortex under eyes closed and eyes open conditions: A resting‐state fMRI study

The thalamus and visual cortex are two key components associated with the alpha power of electroencephalography. However, their functional relationship remains to be elucidated. Here, we employ resting‐state functional MRI to investigate the temporal correlations of spontaneous fluctuations between the thalamus [the whole thalamus and its three largest nuclei (bilateral mediodorsal, ventrolateral and pulvinar nuclei)] and visual cortex under both eyes open and eyes closed conditions. The whole thalamus show negative correlations with the visual cortex and positive correlations with its contralateral counterpart in eyes closed condition, but which are significantly decreased in eyes open condition, consistent with previous findings of electroencephalography desynchronization during eyes open resting state. Furthermore, we find that bilateral thalamic mediodorsal nuclei and bilateral ventrolateral nuclei have remarkably similar connectivity maps, and resemble to those of the whole thalamus, suggesting their crucial contributions to the thalamus‐visual correlations. The bilateral pulvinar nuclei are found to show distinct functional connectivity patterns, compatible with previous findings of the asymmetry of anatomical and functional organization in the nuclei. Our data provides evidence for the associations of intrinsic spontaneous neuronal activity between the thalamus and visual cortex under different resting conditions, which might have implications on the understanding of the generation and modulation of the alpha rhythm. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Topographical organization of the projections from the reticular thalamic nucleus to the intralaminar and medial thalamic nuclei in the cat

The topography of the projections from the reticular nucleus of the thalamus (RT) to the intralaminar and medial thalamic nuclei were studied in the cat by the method of retrograde transport of horseradish peroxidase (HRP). Single small injections of the enzyme were made in the different intralaminar nuclei--mediodorsal, ventromedial, midline, and habenular--and in anterior group nuclei. The location and density of the neuronal labeling in the different parts of the RT were studied in each case. Our results show that 1) after injections located in all the nuclei here studied, a consistent number of labeled neurons were found in the RT, except for the injections in the lateral habenula and the anterior thalamic nuclear complex, both of which did not label neurons in the RT. 2) Among the other thalamic nuclei here studied, the most medially situated receive less numerous RT projections than those most laterally located. 3) Injections in all the nuclei studied gave rise to a cellular labeling in the anterior sectors of the RT, except for the anterior nuclear group and the lateral habenula. The projections from the rostral pole of the RT were topographically mediolaterally organized. 4) The anterodorsal part of the pregeniculate sector of the RT projects upon the large-celled part of the lateral central nucleus and to a lesser extent upon the paracentral, centromedian, and ventromedial nuclei, the anterior part of the lateral central nucleus, and the lateral band of the mediodorsal nucleus. The posterodorsal part of the RT pregeniculate sector only projects to the large-celled part of the lateral central nucleus. The dorsal portion of the posteroventral part of the RT pregeniculate sector also projects upon the large-celled part of the lateral central nucleus; its ventral portion projects to the ventromedial nucleus, the posterior part of the paracentral nucleus, the lateral band of the mediodorsal nucleus, and the centromedian nucleus. 5) The infrageniculate sector of the RT projects to the posterior part of the ventromedial nucleus. A weaker projection to the large-celled part of the lateral central nucleus, the centromedian nucleus, and the lateral band of the mediodorsal nucleus was also observed. 6) The ventral lateral geniculate nucleus projects upon the large-celled part of the lateral central nucleus, the lateral band of the mediodorsal nucleus, and the ventromedial nucleus. All these findings suggest an important modulatory action of the RT on the activity of the thalamic nuclei considered here.     

The volume of the mediodorsal thalamic nucleus in treated and untreated schizophrenics.

Reductions of 40% in total cell number and 25% in volume of the mediodorsal thalamic nucleus were recently reported in an unbiased neurostereological study of neuroleptic-treated schizophrenic patients. In order to investigate whether these results might be secondary to many years of treatment with neuroleptic drugs, eight brains from schizophrenics never treated with neuroleptics and eight controls were studied using the unbiased Cavalieri volume estimator. To compare left-right differences in this region, twelve neuroleptic-treated schizophrenics and eleven control cases were compared. The brains used for the left-right comparison study and five of 20 used for comparison of treated and untreated brain volumes have been used in an earlier study. The mediodorsal thalamus volume was reduced by 31% in untreated schizophrenics and by 22% in neuroleptic-treated schizophrenics. No differences were found in mean total volume of the left and right mediodorsal thalamus in brains from controls nor from schizophrenics. A major difference exists with respect to time of fixation in controls (12 years) and untreated schizophrenics (39 years) that makes shrinkage differences a possible confounding variable. The results suggest that the consistent reduction in number of neurons in the mediodorsal thalamic nucleus are not secondary to prolonged treatment with neuroleptic drugs and that asymmetry in this specific brain region is not a feature of the schizophrenia-afflicted brain.     

The thalamus and schizophrenia: current status of research

The thalamus provides a nodal link for multiple functional circuits that are impaired in schizophrenia (SZ). Despite inconsistencies in the literature, a meta analysis suggests that the volume of the thalamus relative to that of the brain is decreased in SZ. Morphometric neuroimaging studies employing deformation, voxel-based and region of interest methodologies suggest that the volume deficit preferentially affects the thalamic regions containing the anterior and mediodorsal nuclei, and the pulvinar. Postmortem design-based stereological studies have produced mixed results regarding volume and neuronal deficits in these nuclei. This review examines those aspects of thalamic circuitry and function that suggest salience to SZ. Evidence for anomalies of thalamic structure and function obtained from postmortem and neuroimaging studies is then examined and directions for further research proposed.     

Metabolic disconnection between the mediodorsal nucleus of the thalamus and cortical Brodmann's areas of the left hemisphere in schizophrenia

OBJECTIVE: The authors' goal was to examine interregional correlations of thalamocortical metabolic activity during a verbal learning task in schizophrenia. METHOD: They used [18F]fluorodeoxyglucose positron emission tomography in 41 unmedicated patients with schizophrenia and 59 normal comparison subjects. RESULTS: A metabolic disconnection was observed in patients with schizophrenia in the left hemisphere between the mediodorsal nucleus and widespread frontotemporal cortical regions, and stronger-than-normal intercorrelations were found between the pulvinar and superior temporal, selected parietal, posterior cingulate, and occipital areas. CONCLUSIONS: Deficits in the functional interrelationships between the left frontotemporal cortices and the left mediodorsal nucleus of the thalamus complement inferences from postmortem and magnetic resonance imaging volumetric studies identifying a thalamic diathesis in schizophrenia.     

Eyelid tremor in a patient with a unilateral paramedian thalamic lesion

A patient with a circumscribed infarction of the right paramedian thalamus developed a tremor of both eyelids on voluntary eye closure. Co-registration of the magnetic resonance image to a stereotactic atlas of the human thalamus revealed that the lesion was confined to a small subgroup of paramedian nuclei, including the parvocellular part of the mediodorsal nucleus. It is concluded that this region provides inhibitory input to cortical and/or subcortical regions controlling eyelid movements. Voluntary eye closure may involve direct cortico-nuclear connections and indirect pathways through the paramedian thalamus, most probably through the mediodorsal nucleus.     

Volumes of association thalamic nuclei in schizophrenia: a postmortem study

The major association thalamic nuclei, the mediodorsal nucleus (MD) and the medial pulvinar nucleus (PUM) are regarded as important parts of the circuits among association cortical regions. Association cortical regions of the frontal, parietal and temporal lobes have been repeatedly implicated in the neuropathology of schizophrenia. Thus, the aim of the present postmortem study was to investigate the volumes of association thalamic nuclei in this disease. The volumes of the whole thalamus (THAL), MD and PUM were measured in each hemisphere of brains of 12 patients with schizophrenia and 13 age-matched and gender-matched normal control subjects without neuropsychiatric disorders. Patients with schizophrenia exhibited significant volume reductions in both the MD and the PUM, the reductions being more pronounced in the PUM. The volume of the PUM in the left (−19.7%, P=0.02) and right (−22.1%, P=0.01) hemispheres was significantly reduced in the schizophrenia group. The volume of the MD was reduced in both hemispheres in the schizophrenia group. However, the volume reduction was only significant in the left hemisphere (−9.3%, P=0.03). Patients with schizophrenia also exhibited a decreased volume of the THAL in the left (−16.4%, P=0.003) and right (−15.2%, P=0.006) hemispheres. There were no significant correlations between thalamic volumes and duration of illness or age of the patients.

In conclusion, the present data indicate volume reductions of association thalamic nuclei in schizophrenia. These anatomical findings are consistent with the view that schizophrenia may be associated with disturbances of association cortical networks. However, the findings of a substantial volume reduction of the THAL suggest that the volumes of additional thalamic nuclei may be also reduced in schizophrenia.     

Elevated neuron number in the limbic thalamus in major depression

OBJECTIVE: The mediodorsal and anteroventral/anteromedial nuclei of the thalamus are brain regions of interest in the study of mood disorders because they connect subcortical limbic system structures such as the amygdala with the prefrontal, cingulate, and temporal cortices. Anatomical abnormalities have been observed both in the amygdala and in the aforementioned cortical regions in affective disorder patients. Neuroanatomical studies of the thalamus have rarely been conducted in patients with mood disorders. METHOD: Postmortem tissue from the Stanley Foundation Brain Bank was obtained from subjects diagnosed with major depressive disorder, bipolar disorder, and schizophrenia as well as a nonpsychiatric comparison group (N=10-13 per group). The optical disector stereological procedure was used to count neurons in the mediodorsal and anteroventral/anteromedial nuclei of the thalamus in each brain. RESULTS: There were significantly more neurons in the mediodorsal (37%) and anteroventral/anteromedial (26%) nuclei in subjects with major depressive disorder relative to the nonpsychiatric comparison subjects. Neuron numbers and volumes in these limbic thalamic nuclei were normal in the schizophrenia and bipolar subjects. CONCLUSIONS: The data indicate that there is an elevation in total neuron number in the limbic thalamus that is specific for major depressive disorder. This represents the first report of a neuropsychiatric disorder being associated with an increase in total regional neuron number. The present findings, along with recent data, indicate that significant anatomical and functional abnormalities are present in limbic circuits in major depressive disorder.     

Neuropathological study of the dorsal raphe nuclei in late-life depression and Alzheimer's disease with and without depression

OBJECTIVE: Few studies have examined pathological changes in serotonergic neurons in depression, particularly in elderly patients and in elderly patients in which depression occurs in dementia. The authors hypothesized that greater neurofibrillary pathology and fewer serotonergic neurons would be found in the dorsal raphe nuclei in depressed elderly subjects, compared with nondepressed elderly subjects, and in Alzheimer's disease patients with depression, compared to Alzheimer's disease patients without depression. METHOD: In a postmortem study, immunocytochemistry and two-dimensional image analysis were used to measure neuronal density and neuritic pathology in serotonergic neurons in the dorsal raphe nuclei of elderly subjects with primary major depression (N=14), elderly Alzheimer's disease patients with (N=8) and without (N=7) comorbid depression, and nondepressed elderly comparison subjects (N=10). RESULTS: No differences in neuritic pathology or neuronal density were found between the subjects with primary major depression and the nondepressed comparison subjects. The Alzheimer's disease subjects showed markedly fewer serotonergic neurons and associated higher levels of neuritic pathology, compared with the subjects with primary depression and the nondepressed comparison subjects, but the Alzheimer's disease subjects with comorbid major depression did not differ from the Alzheimer's disease subjects without depression on these measures. CONCLUSIONS: The study found no evidence of a loss of serotonergic neurons or of neuritic pathology in the dorsal raphe nuclei in older people with depression, with or without comorbid Alzheimer's disease. These findings suggest that if serotonergic dysfunction occurs in older depressed subjects, it is not due to neuronal loss in the brainstem. Pathophysiological changes may lie elsewhere, such as in the frontal-subcortical circuits.