Structural alterations in brainstem,basal ganglia and thalamus associated with parkinsonism in schizophrenia spectrum disorders

European Archives of Psychiatry and Clinical Neuroscience - The relative roles of brainstem, thalamus and striatum in parkinsonism in schizophrenia spectrum disorder (SSD) patients are largely...     

Structural and functional evolution of the basal ganglia in vertebrates

While a basal ganglia with striatal and pallidal subdivisions is¹ clearly present in many extant anamniote species, this basal ganglia is cell sparse and receives only a relatively modest tegmental dopaminergic input and little if any cortical input. The major basal ganglia influence on motor functions in anamniotes appears to be exerted via output circuits to the tectum. In contrast, in modern mammals, birds, and reptiles (i.e., modern amniotes), the striatal and pallidal parts of the basal ganglia are very neuron-rich, both consist of the same basic populations of neurons in all amniotes, and the striatum receives abundant tegmental dopaminergic and cortical input. The functional circuitry of the basal ganglia also seems very similar in all amniotes, since the major basal ganglia influences on motor functions appear to be exerted via output circuits to both cerebral cortex and tectum in sauropsids (i.e., birds and reptiles) and mammals. The basal ganglia, output circuits to the cortex, however, appear to be considerably more developed in mammals than in birds and reptiles. The basal ganglia, thus, appears to have undergone a major elaboration during the evolutionary transition from amphibians to reptiles. This elaboration may have enabled amniotes to learn and/or execute a more sophisticated repertoire of behaviors and movements, and this ability may have been an important element of the successful adaptation of amniotes to a fully terrestrial habitat. The mammalian lineage appears, however, to have diverged somewhat from the sauropsid lineage with respect to the emergence of the cerebral cortex as the major target of the basal ganglia circuitry devoted to executing the basal ganglia-mediated control of movement.     

A diffusion weighted imaging study of basal ganglia in schizophrenia

Objectives: Several magnetic resonance imaging (MRI) studies provided evidence of selective brain abnormalities in schizophrenia, both in cortical and subcortical structures. Basal ganglia are of particular interest, given not only the high concentration of dopaminergic neurons and receptors, but also for their crucial role in cognitive functions, commonly impaired in schizophrenia. To date, very few studies explored basal ganglia using diffusion imaging, which is sensitive to microstructural organization in brain tissues. The aim of our study is to explore basal ganglia structures with diffusion imaging in a sizeable sample of patients affected by schizophrenia and healthy controls.

Methods: We enrolled 52 subjects affected by schizophrenia according to DMS-IV-R criteria and 46 healthy controls. Diffusion weighted images were obtained using a 1.5 Tesla scanner and apparent diffusion coefficient (ADC) values were determined in axial and coronal sections at the level of basal ganglia.

Results: Patients affected by schizophrenia showed a significantly higher ADC compared to healthy controls in the left anterior lenticular nucleus (F?=?3.9, p?=?.05). A significant positive correlation between right anterior lenticular nucleus and psychotropic dosages was found (r?=?0.4, p?=?.01).

Conclusions: Our study provides evidence of lenticular nucleus microstructure alterations in schizophrenia, potentially sustaining cognitive and motor deficits in schizophrenia.

• Key points

• The basal ganglia structures was explored with diffusion imaging in a sizeable sample of patients affected by schizophrenia and healthy controls.

• Patients affected by schizophrenia showed a significantly higher ADC compared to healthy controls in the left anterior lenticular nucleus.

• Our study provides evidence of lenticular nucleus microstructure alterations in schizophrenia, potentially sustaining cognitive and motor deficits in schizophrenia.

     

No effect of obstetric complications on basal ganglia volumes in schizophrenia

Background

Heterogeneous findings have been reported in studies of basal ganglia volumes in schizophrenia patients as compared to healthy controls. The basal ganglia contain dopamine receptors that are known to be involved in schizophrenia pathology and to be vulnerable to pre- and perinatal hypoxic insults. Altered volumes of other brain structures (e.g. hippocampus and lateral ventricles) have been reported in schizophrenia patients with a history of obstetric complications (OCs). This is the first study to explore if there is a relationship between OCs and basal ganglia volume in schizophrenia.

Methods

Thorough clinical investigation (including information on medication) of 54 schizophrenia patients and 54 healthy control subjects was undertaken. MR images were obtained on a 1.5 T scanner, and volumes of nucleus caudatus, globus pallidum, putamen, and nucleus accumbens were quantified automatically. Information on OCs was blindly collected from original birth records.

Results

Unadjusted estimates demonstrated a relationship between increasing number of OCs and larger volume of nucleus accumbens in schizophrenia patients and healthy controls. No statistically significant relationships were found between OCs and the basal ganglia volumes when controlled for intracranial volume, age, and multiple comparisons. There were no effects of typical versus atypical medication on the basal ganglia volumes. The patients with schizophrenia had larger globus pallidum volumes as compared to healthy controls, but there were no case–control differences for accumbens, putamen, or caudate volumes.

Conclusion

The present results do not support the hypothesis that OCs are related to alterations in basal ganglia volume in chronic schizophrenia.     

Distinct basal ganglia hyperechogenicity in idiopathic basal ganglia calcification

We report a 67‐year‐old patient with idiopathic basal ganglia calcification (IBGC). He presented with progressive cognitive impairment, frontal lobe dysfunction, mild leg spasticity, and levodopa (L ‐dopa)‐responsive parkinsonism. Transcranial sonography (TCS) revealed marked hyperechogenicity of the basal ganglia and periventricular spaces bilaterally. The detected signal alterations showed a fairly symmetric distribution and corresponded to the hyperintense calcifications depicted on the computer tomography brain scan. The combination of symmetric hyperechogenic areas adjacent to the lateral ventricles and of the basal ganglia may serve as an imaging marker characteristic of IBGC. Hyperechogenicity due to extended basal ganglia calcification as presented here is distinct from the pattern of hyperechogenicity caused by heavy metal accumulation, which is described to be less striking. In addition to atypical parkinsonian syndromes such as progressive supranuclear palsy and multiple system atrophy, IBGC is thus another differential diagnosis of parkinsonism with basal ganglia hyperechogenicity. © 2010 Movement Disorder Society.     

Regional patterns and clinical correlates of basal ganglia morphology in non-medicated schizophrenia

Although structural changes of the basal ganglia are widely implicated in schizophrenia, prior findings in chronically medicated patients show that these changes relate to particular antipsychotic treatments. In unmedicated schizophrenia, local alterations in morphological parameters and their relationships with clinical measures remain unknown. Novel surface-based anatomical modelling methods were applied to magnetic resonance imaging data to examine regional changes in the shape and volume of the caudate, the putamen and the nucleus accumbens in 21 patients (19 males/2 females; mean age=30.7+/-7.3) who were either antipsychotic-na?ve or antipsychotic-free for at least 1 year and 21 healthy comparison subjects (19 males/2 females; mean age=31.1+/-8.2). Clinical relationships of striatal morphology were based on exploratory analyses. Left and right global putamen volumes were significantly smaller in patients than controls; no significant global volume effects were observed for the caudate and the nucleus accumbens. However, surface deformation mapping results showed localized volume changes prominent bilaterally in medial/lateral anterior regions of the caudate, as well as in anterior and midposterior regions of the putamen, pronounced on the medial surface. A significant positive correlation was observed between right anterior putamen surface contractions and affective flattening, a core negative symptom of schizophrenia. The diagnostic effects of local surface deformations mostly pronounced in the associative striatum, as well as the correlation between anterior putamen morphology and affective flattening in unmedicated schizophrenia suggest disease-specific neuroanatomical abnormalities and distinct cortical-striatal dysconnectivity patterns relevant to altered executive control, motor planning, along with abnormalities of emotional processing.     

特发性基底节钙化的临床分析

目的探讨特发性基底节钙化的临床特点与头部CT表现,防止漏诊及误诊。方法分析24例特发性基底节钙化的临床特点与头部CT的表现。结果(1)24例病例均为散发;(2)临床表现主要为癫癎发作、锥体外系症状、进行性痴呆、头昏、失眠等,亦可无临床表现,血清钙、磷均正常;(3)头颅CT主要表现为对称性双侧基底节钙化。结论特发性基底节钙化的临床表现无特异性。在排除其它可引起基底节钙化的相关疾病的基础上,头颅CT及实验室检查对本病诊断有重要意义,尤其对无症状者更有意义。     

Multiregional 1H-MRSI of the hippocampus,thalamus, and basal ganglia in schizophrenia

Background: The hippocampus, thalamus and basal ganglia are among the brain regions of major interest in schizophrenia. Aims: The purpose of this study was to corroborate previous findings of reduced N-acetylaspartate in the hippocampal and thalamic regions and to investigate possible metabolite changes in the putamen in schizophrenia. Method: MRSI study of the thalamus, basal ganglia, and hippocampus in 13 schizophrenic patients under stable medication and age-matched healthy controls. Results A decrease of the N-acetylaspartate signal was found in the hippocampal region and the thalamus but not in the putamen of patients compared to controls. No significant group differences in the signals from creatine and phosphocreatine, and choline-containing compounds were found in the hippocampal region and the putamen but the signal from choline-containing compounds was decreased in the thalamus of patients. Conclusion: Metabolic processes in the basal ganglia of schizophrenic patients seem to be opposite the hippocampal and thalamus findings. Received: 6 August 2002 / Accepted: 5 December 2002 Correspondence to Dr. Gabriele Ende     

Dissociation between medial temporal lobe and basal ganglia memory systems in schizophrenia

The purpose of this study was to investigate basal ganglia (BG) and medial temporal lobe (MTL) dependent learning in patients with schizophrenia. Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent (if two stimuli are associated with the same response) increases generalization between them. The learning of stimulus-response pairs is related to the BG, whereas the MTL system participates in stimulus generalization. Forty-three patients with DSM-IV schizophrenia and 28 matched healthy controls participated. Volunteers received the Rutgers acquired equivalence task (face-fish task) by [Myers, C.E., Shohamy, D., Gluck, M.A. et al., 2003. Dissociating hippocampal versus basal ganglia contributions to learning and transfer. J. Cogn. Neurosci. 15, 185-193.], the California Verbal Learning Test (CVLT), and the n-back working memory test. The Rutgers acquired equivalence task investigates BG-dependent processes (stimulus-response learning) and MTL-dependent processes (stimulus generalization) with a single test. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was spared. The stimulus generalization deficit correlated with the CVLT performance (total scores from trials 1-5 and long-delay recall), but not with the n-back test performance. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, this is the first study to show that patients with schizophrenia exhibit deficits during MTL-dependent learning, but not during BG-dependent learning within a single task. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-stiratal system.     

Functional magnetic resonance imaging evidence for disrupted basal ganglia function in schizophrenia

OBJECTIVE: This study was an examination of basal ganglia dysfunction in schizophrenia using functional magnetic resonance imaging (fMRI). METHOD: The authors used a motor sequencing task to investigate activation of the caudate, anterior putamen plus globus pallidus, and posterior putamen plus globus pallidus in eight subjects with schizophrenia and 12 group-matched comparison subjects. Differences in activation of the thalamus, the target of direct output from the globus pallidus, were also examined. RESULTS: The schizophrenia subjects showed significant bilateral deficits in the posterior putamen, globus pallidus, and thalamus but not the anterior putamen plus globus pallidus or caudate. Functional connectivity analysis revealed that the deficits in thalamic activation were related to deficits in posterior putamen and globus pallidus activation. CONCLUSIONS: These results provide fMRI evidence for basal ganglia dysfunction in subjects with schizophrenia and suggest that this deficit results in disrupted outflow to the thalamus. These deficits may underlie the behavioral impairments in goal-directed action observed in schizophrenia.     

Structural findings in the basal ganglia in genetically determined and idiopathic Parkinson's disease

A bilateral compensatory increase of basal ganglia (BG) gray matter value (GMV) was recently demonstrated in asymptomatic Parkin mutation carriers, who likely have an increased risk to develop Parkinson's disease (PD). We hypothesized BG morphological changes in symptomatic Parkin mutation carriers (sPARKIN-MC) and idiopathic PD patients (iPD) after the occurrence of PD symptoms, reflecting the breakdown of compensatory mechanisms. Nine sPARKIN-MC, 14 iPD, and 24 controls were studied clinically and with voxel-based morphometry. Analysis of variance revealed mainly BG decrease of GMV in sPARKIN-MC and to a lesser extent in iPD. However, a slight increase in GMV was also found in the right globus pallidus externus in sPARKIN-MC and in the right putamen in iPD. This may reflect a structural correlate of functional compensation that can only partially be maintained when nigrostriatal neurodegeneration becomes manifest. Simple regression analyses with the UPDRS-III and disease duration score revealed a distinct more bilateral linear decrease of BG GMV in sPARKIN-MC than in iPD that may correspond to previous findings showing a symmetric reduction in putaminal (18)F-DOPA-uptake and bilateral manifestation of symptoms in sPARKIN-MC. In symptomatic PD, BG are subject to a progressive atrophy, which gradually increases with disease severity and duration.     

Nonlinear analysis of discharge patterns in monkey basal ganglia

Spontaneous discharge of basal ganglia neurons is often analyzed with time- or frequency-domain methods. However, it has been shown that sequences of inter-spike interval series are not fully described by such linear procedures. We therefore carried out a characterization of the nonlinear features of spontaneous discharge of neurons in the primate basal ganglia. We studied the spontaneous activity of neurons in the subthalamic nucleus (22 cells), as well as neurons in the external and internal pallidal segments (53 and 39 cells, respectively), recorded with standard extracellular recording methods in two awake Rhesus monkeys. As a measure of the statistical irregularity of neuronal discharge, we compared the approximate entropy of inter-spike interval sequences with that of shuffled representations of the same data. In all three basal ganglia structures, approximately 95% of the original data showed lower approximate entropy values than the shuffled data, suggesting a temporal organization in the original sequence. Fano factor analysis confirmed the presence of a temporal organization of inter-spike interval sequences, and indicated the presence of self-similarity in the great majority of them. In addition, Hurst exponent analysis showed that the inter-spike interval series are persistent. Hurst exponents often differ between short and long scaling ranges. Subsequent principal component analyses allowed us to identify three distinct patterns of the temporal evolution of inter-spike interval sequences in the phase space. These types were found in varying distributions in all three nuclei. Our analyses demonstrate that the discharge of most neurons in the basal ganglia of awake monkeys has nonlinear features that may be important for information coding in the basal ganglia.     

Epigenetic mechanisms expressed in basal ganglia GABAergic neurons differentiate schizophrenia from bipolar disorder

In the cerebral prefrontal cortex (PFC), DNA-methyltransferase 1 (DNMT1), the enzyme that catalyzes the methylation of cytosine at carbon atoms in position 5 in CpG dinucleotides, is expressed selectively in GABAergic neurons and is upregulated in layers I and II of schizophrenia (SZ) and bipolar disorder patients with psychosis (BDP). To replicate these earlier findings and to verify whether overexpression of DNMT1 and the consequent epigenetic decrease of reelin and glutamic acid decarboxylase (GAD) 67 mRNA expression also occur in GABAergic medium spiny neurons of the caudate nucleus (CN) and putamen (PT) of SZ and BDP, we studied the entire McLean 66 Cohort (Harvard Brain Tissue Resource Center, McLean Hospital, Belmont, MA) including SZ and BDP, which were matched with nonpsychiatric subjects. The data demonstrate that in GABAergic medium spiny neurons of CN and PT, unlike in GABAergic neurons of layer I and II PFC, the increased expression of DNMT1 and the decrease of reelin and GAD67 occur in SZ but not in BDP. This suggests that different epigenetic mechanisms must exist in the pathogenesis underlying SZ and BDP and implies that these disorders might involve two separate entities that are characterized by a well-defined neuropathology.     

Frontal lobes, basal ganglia, temporal lobes--three sites for schizophrenia?

This special issue of the Schizophrenia Bulletin focuses on three brain areas hypothesized to play a role in the etiology of schizophrenia--the frontal lobes, the basal ganglia, and the temporal lobes. Contributors to the issue review evidence from brain-imaging, post-mortem, and psychopharmacological studies that support the involvement of each of these important brain areas in schizophrenia. It is concluded that theories emphasizing cortical/subcortical interconnections rather than a single brain area provide the greatest challenge, and also the greatest promise, to schizophrenia researchers.     

An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone

OBJECTIVE: The basal ganglia may contribute to extrapyramidal movement disorders, affective disturbances, and cognitive deficits in schizophrenia. Basal ganglia volumes are putatively affected by antipsychotic medications. The purpose of this study was to determine the long-term effects of risperidone treatment in a cohort of first-episode patients with schizophrenia. METHOD: The subjects were 30 patients with first-episode schizophrenia, 12 patients chronically treated with typical antipsychotics, and 23 healthy comparison subjects. They were scanned by magnetic resonance imaging at baseline. The first-episode patients received 1 year of continuous risperidone treatment, after which they and the comparison subjects were rescanned. Caudate, putamen, and globus pallidus volumes were determined from coronal images. RESULTS: The baseline caudate, putamen, and globus pallidus volumes were significantly larger in the chronically treated patients than in the untreated first-episode subjects and comparison subjects. These volumes did not differ between the first-episode patients and healthy comparison subjects. Basal ganglia volumes were unchanged after 1 year of exposure to risperidone in the first-episode subjects. Extrapyramidal movement disorders were present in the majority of chronically treated patients and more than one-third of the never-medicated first-episode patients at baseline. CONCLUSIONS: This group of first-episode patients did not exhibit abnormalities of basal ganglia volumes, nor were basal ganglia volumes affected by exposure to risperidone. Movement disorders were observed in both first-episode and chronically treated patients, suggesting effects of both illness and medications.     

Developmental reflexes and 31P Magnetic Resonance Spectroscopy of basal ganglia in antipsychotic-naive schizophrenia

The study examined the high energy-phosphate metabolism of basal ganglia in antipsychotic-naive schizophrenia patients with and without developmental reflexes in comparison to healthy subjects. Nineteen antipsychotic-naive schizophrenics of whom 11 had developmental reflexes and 26 age-sex-matched healthy subjects without developmental reflexes underwent in-vivo 2-D 31P Magnetic Resonance Spectroscopy of basal ganglia on a 1.5-T scanner. Mean age-at-onset of psychosis was significantly lower in patients with developmental reflexes. Mean PCr/Total ATP ratio in bilateral basal ganglia was lower in patients than healthy subjects. The ratio was the least in patients with developmental reflexes (F=10.7; df=2, 42; p<0.001). Schizophrenia patients with developmental reflexes had the lowest PCr/Total ATP ratio in basal ganglia indicating more severe metabolic abnormality. These patients had younger age-at-onset of psychosis. Together, this suggests neurodevelopmental etiopathogenesis in schizophrenia.     

Multisensory integration in the basal ganglia

Sensorimotor co-ordination in mammals is achieved predominantly via the activity of the basal ganglia. To investigate the underlying multisensory information processing, we recorded the neuronal responses in the caudate nucleus (CN) and substantia nigra (SN) of anaesthetized cats to visual, auditory or somatosensory stimulation alone and also to their combinations, i.e. multisensory stimuli. The main goal of the study was to ascertain whether multisensory information provides more information to the neurons than do the individual sensory components. A majority of the investigated SN and CN multisensory units exhibited significant cross-modal interactions. The multisensory response enhancements were either additive or superadditive; multisensory response depressions were also detected. CN and SN cells with facilitatory and inhibitory interactions were found in each multisensory combination. The strengths of the multisensory interactions did not differ in the two structures. A significant inverse correlation was found between the strengths of the best unimodal responses and the magnitudes of the multisensory response enhancements, i.e. the neurons with the weakest net unimodal responses exhibited the strongest enhancement effects. The onset latencies of the responses of the integrative CN and SN neurons to the multisensory stimuli were significantly shorter than those to the unimodal stimuli. These results provide evidence that the multisensory CN and SN neurons, similarly to those in the superior colliculus and related structures, have the ability to integrate multisensory information. Multisensory integration may help in the effective processing of sensory events and the changes in the environment during motor actions controlled by the basal ganglia.     

Macro-aneurysm in the basal ganglia region

A 59-year-old female patient suddenly developed vomiting and gait disturbances followed by decreasing consciousness. CT scans revealed a hemorrhage within the left basal ganglia region with rupture into the ventricles and consecutive hydrocephalus. On angiography an aneurysm in the region of the caput nuclei caudati was shown to be the source of the bleeding. On repeat-angiography 4 months later the aneurysm was no longer visualized, probably due to thrombosis. This is an extraordinary case of a basal ganglia aneurysm comparable with the aneurysms of Willis' circle, but located in a region where generally microaneurysms — mostly combined with hypertension or moyamoya disease can be found.