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Volume Changes in Gray Matter in First-Episode Neuroleptic-Naive Schizophrenic Patients Treated With Risperidone
Abstract
Structural neuroimaging techniques have consistently shown that treatment of schizophrenic patients with conventional antipsychotics causes an increase in basal ganglia volume. However, findings in schizophrenic patients treated with the newer atypical antipsychotic drugs are less consistently reported. To explore this issue, the authors used a whole-brain, unbiased, and automated technique for comparing brain structural features across scans in schizophrenic patients before and after a treatment with the atypical antipsychotic risperidone. T1-weighted images from 11 first-episode neuroleptic-naive schizophrenic patients were processed and analyzed for regions of interest (basal ganglia) by using optimized voxel-based morphometry. Scans were repeated after 3 months of continuous treatment with risperidone. Region of interest-based voxel-based morphometry analyses revealed increases in gray matter volume for the right and left caudate nuclei and for the left accumbens after the treatment with risperidone. Hence, in our sample of schizophrenic patients, treatment with risperidone was associated, in contrast to the findings for other atypical antipsychotics, with an increase in basal ganglia volume. Such discrepancy could be related to the pharmacodynamics of risperidone (the atypical antipsychotic showing the higher affinity for D2 receptors) and the rather high mean doses used in our study (ie, 6.05 mg/d).
... Among the 85 studies that were found according to our searching strategy, 19 (14,15,20,(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) of them met the inclusion criteria and were enrolled. Additional 17 (16,17,(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54) studies were found in other sources: five studies (50-54) came from a review (55), 4 studies (16, 46-48) came from another review (19), the co-author of 3 studies (40,43,45), 2 studies (17, 41) and one study (42) came from three research centers, respectively, which were same as the included studies through our searching strategy, one study (44) came from our group and one study (49) came from a reference list of a included study (37). All additional studies included 9 structural studies (16,44,(48)(49)(50)(51)(52)(53)(54) and 8 functional studies (17,(40)(41)(42)(43)(45)(46)(47) (17, 20, 24-26, 31, 34, 38, 40-43, 45-47) on brain function (Figure 1). ...
... Additional 17 (16,17,(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54) studies were found in other sources: five studies (50-54) came from a review (55), 4 studies (16, 46-48) came from another review (19), the co-author of 3 studies (40,43,45), 2 studies (17, 41) and one study (42) came from three research centers, respectively, which were same as the included studies through our searching strategy, one study (44) came from our group and one study (49) came from a reference list of a included study (37). All additional studies included 9 structural studies (16,44,(48)(49)(50)(51)(52)(53)(54) and 8 functional studies (17,(40)(41)(42)(43)(45)(46)(47) (17, 20, 24-26, 31, 34, 38, 40-43, 45-47) on brain function (Figure 1). ...
... In these two studies, it was showed that the reductions in positive symptoms were associated with striatal volume increases after the administration of antipsychotics (27), while striatal volume loss was related to low quetiapine dose (16). As to the subregions of striatum, such as the caudate and putamen, their gray matter consistently increased in patients after antipsychotic treatment (15,49,53,54). Interestingly, there was a significant sex effect on the relationship between atypical neuroleptic exposure and changes in the structure of the caudate over time (54). ...
A large number of neuroimaging studies have detected brain abnormalities in first-episode schizophrenia both before and after treatment, but it remains unclear how these abnormalities reflect the effects of antipsychotic treatment on the brain. To summarize the findings in this regard and provide potential directions for future work, we reviewed longitudinal structural and functional imaging studies in patients with first-episode schizophrenia before and after antipsychotic treatment. A total of 36 neuroimaging studies was included, involving 21 structural imaging studies and 15 functional imaging studies. Both anatomical and functional brain changes in patients after treatment were consistently observed in the frontal and temporal lobes, basal ganglia, limbic system and several key components within the default mode network (DMN). Alterations in these regions were affected by factors such as antipsychotic type, course of treatment, and duration of untreated psychosis (DUP). Over all we showed that: (a) The striatum and DMN were core target regions of treatment in schizophrenia, and their changes were related to different antipsychotics; (b) The gray matter of frontal and temporal lobes tended to reduce after long-term treatment; and (c) Longer DUP was accompanied with faster hippocampal atrophy after initial treatment, which was also associated with poorer outcome. These findings are in accordance with previous notions but should be interpreted with caution. Future studies are needed to clarify the effects of different antipsychotics in multiple conditions and to identify imaging or other biomarkers that may predict antipsychotic treatment response. With such progress, it may help choose effective pharmacological interventional strategies for individuals experiencing recent-onset schizophrenia.
... All studies were written in English and published between 1996 and 2011. Overall, six compounds (two classified as FGAs and four as SGAs) have been subject to investigation: haloperidol in 2 studies [4,38]; zuclophentizol in 1 study [39]; risperidone in 5 studies [38][39][40][41][42]; olanzapine in 4 studies [4,38,42,43]; clozapine in 4 studies [11,[44][45][46]; and quetiapine in 2 studies [47,48]. The follow-up period ranged from 3-24 months. ...
... In 2005 Massana et al. [40] published a longitudinal study with 11 patients (age range 18-30 years; mean age 23 years) with a diagnosis of schizophrenia or schizophreniform disorder. All patients were first-episode and antipsychotic-naïve at the baseline MRI scanning. ...
... By sorting the findings in columns based on duration of intervention [ Table 1] we intended to capture potential effect of the duration of treatment period on brain structure. The only pattern we prudently infer from this is, that 'short term' risperidone treatment (3 months) may increase BG volumes [39,40], and that this effect may be reversed after 12 months risperidone treatment [38,41,42]. ...
Introduction:
Exposure to antipsychotic medication has been extensively associated with structural brain changes in the basal ganglia (BG). Traditionally antipsychotics have been divided into first and second generation antipsychotics (FGAs and SGAs) however, the validity of this classification has become increasingly controversial. To address if specific antipsychotics induce differential effects on BG volumes or whether volumetric effects are explained by FGA or SGA classification, we reviewed longitudinal structural magnetic resonance imaging (MRI) studies investigating effects of antipsychotic monotherapy.
Material and methods:
We systematically searched PubMed for longitudinal MRI studies of patients with schizophrenia or non-affective psychosis who had undergone a period of antipsychotic monotherapy. We used specific, predefined search terms and extracted studies were hand searched for additional studies.
Results:
We identified 13 studies published in the period from 1996 to 2011. Overall six compounds (two classified as FGAs and four as SGAs) have been investigated: haloperidol, zuclophentixol, risperidone, olanzapine, clozapine, and quetiapine. The follow-up period ranged from 3-24 months. Unexpectedly, no studies found that specific FGAs induce significant BG volume increases. Conversely, both volumetric increases and decreases in the BG have been associated with SGA monotherapy.
Discussion:
Induction of striatal volume increases is not a specific feature of FGAs. Except for clozapine treatment in chronic patients, volume reductions are not restricted to specific SGAs. The current review adds brain structural support to the notion that antipsychotics should no longer be classified as either FGAs or SGAs. Future clinical MRI studies should strive to elucidate effects of specific antipsychotic drugs.
... Striatal volume reductions over time have been reported in some previous studies of FEP patients (Theberge et al. 2007;Boonstra et al. 2011) and at-risk-mental state (ARMS) patients who were treatment naive (Smieskova at al. 2013). However, other studies have reported increased putaminal and caudate volume (Massana et al. 2005;Glenthoj et al. 2007;Roiz-Santiánez et al. 2014) or no significant volumetric differences between FEP patients and HCs (Lang et al. 2001;Haukvik et al. 2016) (see Table 1). Long exposure to antipsychotic medications has also been linked to increased striatal volume (Okugawa et al. 2007; van Haren et al. 2007). ...
... with volume reduction in the dorsal striatum may be related to a subregional striatal response to antipsychotic medication (Massana et al. 2005;Roiz-Santiánez et al. 2014). Additionally, no association was noted between cumulative antipsychotic medication and cortical thinning of the LLOFR, which is consistent with studies in both FEP (Gutiérrez-Galve et al. 2014) and in established schizophrenia (Cobia et al. 2012), suggesting that regional cortical thinning is an inherent feature of progressive psychotic illness (Nesvag et al. 2008) and may reflect an underlying neuropathophysiological process associated with psychosis onset. ...
The location, extent and progression of longitudinal morphometric changes after first-episode of psychosis (FEP) remains unclear. We investigated ventricular and cortico-subcortical regions over a 3-year period in FEP patients compared with healthy controls. High resolution 1.5T T1-weighted MR images were obtained at baseline from 28 FEP patients at presentation and 28 controls, and again after 3-years. The longitudinal FreeSurfer pipeline (v.5.3.0) was used for regional volumetric and cortical reconstruction image analyses. Repeated-measures ANCOVA and vertex-wise linear regression analyses compared progressive changes between groups in subcortical structures and cortical thickness respectively. Compared with controls, patients displayed progressively reduced volume of the caudate [F(1,51)=5.86, p=0.02, Hedges’ g=0.66], putamen [F(1,51)=6.06, p=0.02, g=0.67] ,thalamus [F(1,51)=6.99, p=0.01, g=0.72] and increased right lateral ventricular volume [F(1, 51)=4.03, p=0.05], and significantly increased rate of cortical thinning [F(1,52)=5.11, p=0.028)] at a mean difference of 0.84% [95% CI (0.10, 1.59)] in the left lateral orbitofrontal region over the 3-year period. In patients, greater reduction in putamen volume over time was associated with lower cumulative antipsychotic medication dose (r=0.49, p=0.01), and increasing lateral ventricular volume over time was associated with worsening negative symptoms (r=0.41, p=0.04) and poorer global functioning (r=-0.41, p=0.04). This study demonstrates localised progressive structural abnormalities in the cortico-striato-thalamo-cortical circuit after the onset of psychosis, with increasing ventricular volume noted as a neuroanatomical marker of poorer clinical and functional outcome.
... Overall, our findings considered together with previous research found that subcortical volume loss 7,42-45 and cortical thinning 6,46 occur during clozapine treatment and may indicate that these changes may emerge within the first months of clozapine treatment and further progresses over longer periods of administration. Treatment with non-clozapine antipsychotics is associated with increases in caudate and putamen volume [80][81][82][83][84][85][86][87][88][89] . Therefore, the observed decreases in caudate and putamen volume after switching to clozapine treatment could indicate a reversal of the volumetric increases associated with prior nonclozapine antipsychotic treatment and/or effects of discontinuing treatment with non-clozapine antipsychotics. ...
The neurobiological effects of clozapine are under characterised. We examined the effects clozapine treatment on subcortical volume and cortical thickness and investigated whether macrostructural changes were linked to alterations in glutamate or N-acetylaspartate (NAA). Data were acquired in 24 patients with treatment-resistant schizophrenia before and 12 weeks after switching to clozapine. During clozapine treatment we observed reductions in caudate and putamen volume, lateral ventricle enlargement (P < 0.001), and reductions in thickness of the left inferior temporal cortex, left caudal middle frontal cortex, and the right temporal pole. Reductions in right caudate volume were associated with local reductions in NAA (P = 0.002). None of the morphometric changes were associated with changes in glutamate levels. These results indicate that clozapine treatment is associated with subcortical volume loss and cortical thinning and that at least some of these effects are linked to changes in neuronal or metabolic integrity.
... Striatal alterations are a well-known trait of schizophrenia patients (Ebdrup et al., 2010;Stegmayer et al., 2014;Okada et al., 2016) and also in subjects in the MIS model (Casquero-Veiga et al., 2019). When we explored whether these alterations could be influenced by the MIN treatment, we observed similar results with a less restrictive significance threshold than the one shown before in VH and MIS animals (supplementary Figure 1), suggesting that MIN is not able to counteract this striatal GM reduction compared with antipsychotics such as haloperidol (Konradi and Heckers, 2001;Andersson et al., 2002) or risperidone (Massana et al., 2005;Casquero-Veiga et al., 2019). ...
Background
Minocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia related deficits in the maternal immune stimulation (MIS) animal model.
Methods
On gestational day 15, Poly I:C or vehicle were injected to pregnant Wistar rats. 93 male offspring received MIN (30 mg/Kg) or saline from postnatal day (PND) 35-49. At PND70, rats were submitted to the prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.
Results
MIN treatment did not prevent PPI behavioral deficits in MIS-offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).
Conclusions
MIN-treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2–ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.
... Given that many patients included in our meta-analysis were undergoing medication at the time of the scan (Table S5), this variable is likely to have some impact on the COA-O network. However, there is some evidence that suggests that medication alone is unable to explain our results: first, morphological effects of medication are often found to be localized to restricted regions, such as medial temporal lobe and subgenual cortex with lithium ( Germaná et al., 2010 ;Hafeman et al., 2012 ) and BG with antipsychotics ( Navari and Dazzan, 2009 ), while our increase nodes are situated in many other brain areas; second, some studies report that medications could attenuate pathological decreases rather than increase GM volume in patients compared to controls ( Hibar et al., 2016 ;Sarrazin et al., 2019 ;Sheline et al., 2003 ;Wada et al., 2005 ;Zung et al., 2016 ); third, atypical antipsychotics, although found by some to be neurotrophic and induce neurogenesis ( Bai et al., 2003 ;Halim et al., 2004 ;Park et al., 2006 ;Wakade et al., 2002 ;Wang et al., 2004 ) produced mixed volumetric findings ( Massana et al., 2005 ;Navari and Dazzan, 2009 ) but often no increase effects were found in the BG ( Chakos et al., 1995 ;Frazier et al., 1996 ;Lang et al., 2004Lang et al., , 2001Scheepers et al., 2001 ;Westmoreland Corson et al., 1999 ). Moreover, a study reports an absence of increased volume of BG also for typical antipsychotics ( Kreczmanski et al., 2007 ); fourth, anticonvulsant drugs, used in the treatment of bipolar disorder but also for epilepsy (the only neurological disease with a non-negligible number of experiments in our database) showed to produce decreases or no effect ( Abé et al., 2016 ;Chang et al., 2009 ;Germaná et al., 2010 ;Hibar et al., 2018 ); fifth, the increased striatal volume of relatives of schizophrenic patients suggests a genetic factor ( Oertel-Knöchel et al., 2012 ). ...
Numerous studies have investigated gray matter (GM) volume changes in diverse patient groups. Reports of disorder-related GM reductions are common in such work, but many studies also report evidence for GM volume increases in patients. It is unclear whether these GM increases and decreases are independent or related in some way. Here, we address this question using a novel meta-analytic network mapping approach. We used a coordinate-based meta-analysis of 64 voxel-based morphometry studies of psychiatric disorders to calculate the probability of finding a GM increase or decrease in one region given an observed change in the opposite direction in another region. Estimating this co-occurrence probability for every pair of brain regions allowed us to build a network of concurrent GM changes of opposing polarity. Our analysis revealed that disorder-related GM increases and decreases are not independent; instead, a GM change in one area is often statistically related to a change of opposite polarity in other areas, highlighting distributed yet coordinated changes in GM volume as a function of brain pathology. Most regions showing GM changes linked to an opposite change in a distal area were located in salience, executive-control and default mode networks, as well as the thalamus and basal ganglia. Moreover, pairs of regions showing coupled changes of opposite polarity were more likely to belong to different canonical networks than to the same one. Our results suggest that regional GM alterations in psychiatric disorders are often accompanied by opposing changes in distal regions that belong to distinct functional networks.
... 26,88 It may be thus suggested that our basal ganglia findings predominantly reflect brain changes intrinsic to the pathology of psychosis, but that such changes could also be affected by disease processes 17 and persistent exposure to dopamine D 2 receptor antagonists. 89 Likewise, given the possibility that antidepressants also cause thalamic atrophy, 76 the effect of antidepressants is another consideration for the discrepant thalamic findings. 41 The absence of amygdalar and hippocampal volume changes in our ARMS group was consistent with previous ARMS studies, 30,46,[49][50][51][52] supporting longitudinal atrophy in these regions during the course of psychosis. ...
Previous structural magnetic resonance imaging studies of psychotic disorders have demonstrated volumetric alterations in subcortical (ie, the basal ganglia, thalamus) and temporolimbic structures, which are involved in high-order cognition and emotional regulation. However, it remains unclear whether individuals at high risk for psychotic disorders with minimal confounding effects of medication exhibit volumetric changes in these regions. This multicenter magnetic resonance imaging study assessed regional volumes of the thalamus, caudate, putamen, nucleus accumbens, globus pallidus, hippocampus, and amygdala, as well as lateral ventricular volume using FreeSurfer software in 107 individuals with an at-risk mental state (ARMS) (of whom 21 [19.6%] later developed psychosis during clinical follow-up [mean = 4.9 years, SD = 2.6 years]) and 104 age- and gender-matched healthy controls recruited at 4 different sites. ARMS individuals as a whole demonstrated significantly larger volumes for the left caudate and bilateral lateral ventricles as well as a smaller volume for the right accumbens compared with controls. In male subjects only, the left globus pallidus was significantly larger in ARMS individuals. The ARMS group was also characterized by left-greater-than-right asymmetries of the lateral ventricle and caudate nucleus. There was no significant difference in the regional volumes between ARMS groups with and without later psychosis onset. The present study suggested that significant volume expansion of the lateral ventricle, caudate, and globus pallidus, as well as volume reduction of the accumbens, in ARMS subjects, which could not be explained only by medication effects, might be related to general vulnerability to psychopathology.
... PET is also suggested for predicting extrapyramidal side effects from antipsychotic treatment [102]. Accumulating studies suggest dosage adjusted effects of risperidone and zuclopenthixol on cognitive functions in first episode drug-naive schizophrenic patients [103] or effect of risperidone on the volume of gray matter first episode drug-naive schizophrenic patients [104], effects of clozapine and risperidone in relation to cortical thinning in FES [105] or Clozapine association with progressive brain atrophy and cortical thinning in SZ [99]. In long-term antipsychotic treatment, if switching from typical to atypical antipsychotic medication was present, reduction in basal ganglia and thalamus volume was found [106]. ...
This chapter presents an overview of accumulating neuroimaging data with emphasis on translational potential. The subject will be described in the context of three disease states, i.e., schizophrenia, bipolar disorder, and major depressive disorder, and for three clinical goals, i.e., disease risk assessment, subtyping, and treatment decision.
... 112 Increased bilateral caudate nuclei and left accumbens GM volumes have been shown after treatment with risperidone. 113 Furthermore, the efficacy of psychosis treatment with atypical antipsychotics is related to alterations in functional corticostriatal circuitry. 114 A previous study randomly allocated 22 patients with schizophrenia to the CRT group or occupational therapy group. ...
Patients with schizophrenia experience cognitive impairments that relate to poorer social functioning even after amelioration of positive symptoms. Pharmacological treatment and cognitive remediation are the two important therapeutic approaches for cognitive impairment in schizophrenia. Cognitive remediation therapy (CRT) for schizophrenia improves cognitive functioning and induces neuroplasticity. However, different approaches and durations of CRT and different neuroimaging devices have led to variable results in meta‐analyses. The objective of this review is to explore the impact of CRT on neurobiology. Several studies have provided evidence of increased activation in the frontal brain regions, such as the prefrontal cortex, anterior cingulate cortex, and parietal and occipital regions during working memory or executive function tasks after CRT. Two studies have shown alterations in resting‐state connectivity between the prefrontal cortex and temporal regions. Two studies have reported that CRT induces changes in gray matter volume in the hippocampus. Further, one study observed that patients who had received CRT exhibited elevated fractional anisotropy values in the basal ganglia. We conclude that neuroimaging studies assessing CRT in patients with schizophrenia showed functional, structural, and connectivity changes that were positively correlated with cognitive improvements despite heterogeneous CRT approaches. Future studies that combine multiple modalities are required to address the differences, effects of intrinsic motivation, and pharmacological augmentation of CRT. Further understanding of the biological basis might lead to predictions of the CRT response in patients with schizophrenia and contribute to identification of schizophrenic patients for future interventions. This article is protected by copyright. All rights reserved.
... Thus, the inclusion criteria per se prevented us from enrolling drug-free patients. Although the patient groups did not significantly differ in terms of CPZ equivalents and although it is unlikely that antipsychotics alone may explain regionally specific changes between similarly treated patient subgroups, drug effects cannot be entirely excluded [61][62][63]. Eventually, the nAVH subgroup included both individuals who never experienced AVH during the course of their illness and patients who had AVH in the past but were fully remitted at least 1 year prior to scanning. ...
There is growing evidence that the cerebellum plays a crucial role in the pathophysiology of schizophrenia symptoms. Despite increasing evidence for cerebellar involvement in affective, attentive, and cognitive functions including language processing and perception, investigations of cerebellar contributions to auditory verbal hallucinations (AVH) in schizophrenia are lacking. Using structural magnetic resonance imaging at 3T, we investigated the data of 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH (pAVH), whereas the remaining ten patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Employing cerebellum-optimized segmentation techniques, i.e., the Spatially Unbiased Infratentorial Template (SUIT) toolbox, we investigated cerebellar gray matter volume (GMV) differences among the pAVH, nAVH, and a healthy control group, the magnitude of their expression between these groups and the relationship between GMV and schizophrenia symptom load. Lower GMV in pAVH patients compared to controls was found in lobules VIIb and VIIIa. Additionally, lower GMV in pAVH compared to nAVH patients was found in lobule VIIIa. A negative relationship between VIIIa GMV and overall positive symptoms was detected. Correlations with AVH-specific psychometric scores were not significant. This study shows that there are structural changes in the cognitive regions of the cerebellum that are linked to a clinical phenotype presenting with persistent positive symptoms such as AVH. The results suggest that the cerebellum and its associated neural circuits do play a role in the emergence of positive symptoms in schizophrenia, but probably not exclusively in AVH symptom expression.
... This finding confirms results of an earlier study suggesting that SGAs do not produce an increase in basal ganglia volume (Corson et al., 1999). However, a recent study of patients with neuroleptic-naive, first-episode schizophrenia reported an increase in basal ganglia volume in patients treated with risperidone (Massana et al., 2005). In addition, Molina et al. (2005) found increases in gray matter volume in neuroleptic-naive patients treated with risperidone and neuroleptic-resistant patients treated with clozapine (Molina et al., 2005). ...
... These changes may represent illness progression (Lieberman et al., 2001), although some evidence suggests that they are related to antipsychotic treatment per se Andreasen et al., 2013;Fusar-Poli et al., 2013). A few studies have investigated the acute treatment effects in firstepisode samples, and although the findings are inconsistent they report regional brain morphological changes during this period (Massana et al., 2005;Lieberman et al., 2005;Girgis et al., 2006;Glenthoj et al., 2007;Li et al., 2012;Szeszko et al., 2014). A direct relationship to antipsychotic treatment is suggested by the finding that some of these changes were significantly correlated with antipsychotic efficacy, with improvements in psychopathology being associated with increased volumes in several brain regions Li et al., 2012;Goghari et al., 2013), a finding which is contrary to longer term studies describing reductions in brain volumes. ...
We investigated whether morphological brain changes occurred in brain regions associated with body-weight homeostasis during acute antipsychotic treatment, and if so, whether they were related to changes in body mass and metabolic profile. Twenty-two antipsychotic-naive patients with first-episode schizophrenia received either risperidone long acting injection or flupenthixol decanoate over 13 weeks and were compared by structural MRI with 23 matched healthy volunteers at weeks 0, 4 and 13. Images were reconstructed using freesurfer fully-automated whole brain segmentation. The ventral diencephalon and prefrontal cortex were selected to represent the homeostatic and hedonic food intake regulatory systems respectively. Body mass was measured at weeks 0, 7 and 13 and fasting glucose and lipid profiles at weeks 0 and 13. Linear mixed effect models indicated significant group(⁎)time interactions for the ventral diencephalon volumes bilaterally. Ventral diencephalon volume reduction was strongly correlated bilaterally with body mass increase and HDL-cholesterol reductions, and unilaterally with blood glucose elevation. There were no significant changes in prefrontal cortical thickness. These findings implicate the ventral diencephalon, of which the hypothalamus is the main component, in the acute adipogenic and dyslipidaemic effects of antipsychotic medication.
Copyright © 2015. Published by Elsevier Ireland Ltd.
... However, controlling for total brain volume, medicated patients showed a trend towards predominantly increased regional volumes in cerebellum and right inferior parietal lobule in comparison to neuroleptic-naïve patients. The issue of cortical and basal ganglia volumetric changes associated with antipsychotics is a hotly debated topic with various studies reporting decrease in cortical and subcortical volumes (e.g., [36,37] (review)); increase in volume of basal ganglia structures (e.g., [38]), as well as conflicting findings of differential effects of typical and atypical antipsychotics (e.g., [13] (review), [39][40][41]) on brain. Increased brain volumes in medicated vs. neuroleptic-naïve patients with schizophrenia have been previously reported [36,42]. ...
Background:
Brain morphometric abnormalities in schizophrenia have been extensively reported in the literature. Whole-brain volumetric reductions are almost universally reported by most studies irrespective of the characteristics of the samples studied (e.g., chronic/recent-onset; medicated/neuroleptic-naïve etc.). However, the same cannot be said of the reported regional morphometric abnormalities in schizophrenia. While certain regional morphometric abnormalities are more frequently reported than others, there are no such abnormalities that are universally reported across studies. Variability of socio-demographic and clinical characteristics across study samples as well as technical and methodological issues related to acquisition and analyses of brain structural images may contribute to inconsistency of brain morphometric findings in schizophrenia. The objective of the present study therefore was to systematically examine brain morphometry in patients with recent-onset schizophrenia to find out if there are significant whole-brain or regional volumetric differences detectable at the appropriate significance threshold, after attempting to control for various confounding factors that could impact brain volumes.
Methods:
Structural magnetic resonance images of 90 subjects (schizophrenia = 45; healthy subjects = 45) were acquired using a 3 Tesla magnet. Morphometric analyses were carried out following standard analyses pipelines of three most commonly used strategies, viz., whole-brain voxel-based morphometry, whole-brain surface-based morphometry, and between-group comparisons of regional volumes generated by automated segmentation and parcellation.
Results:
In our sample of patients having recent-onset schizophrenia with limited neuroleptic exposure, there were no significant whole brain or regional brain morphometric abnormalities noted at the appropriate statistical significance thresholds with or without including age, gender and intracranial volume or total brain volume in the statistical analyses.
Conclusions:
In the background of the conflicting findings in the literature, our findings indicate that brain morphometric abnormalities may not be directly related to the schizophrenia phenotype. Analysis of the reasons for the inconsistent results across studies as well as consideration of alternate sources of variability of brain morphology in schizophrenia such as epistatic and epigenetic mechanisms could perhaps advance our understanding of structural brain alterations in schizophrenia.
... On the other hand, risperidone treatment increased GM volume in the right and left caudate nuclei and the left accumbens in 11 FEP patients after three months of treatment. In this latter study, it is worth noting that the dose of risperidone (605 mg/day, in CPZ equivalents) was more than twice higher than the usual dose used in the most of neuroimagen studies [24]. In 2005, Molina et al. obtained similar results in a longitudinal study during two years. ...
The findings about the progressive brain changes in schizophrenia are controversial, and the potential confounding effect of antipsychotics on brain structure is still under debate. The goal of the current article was to review the existing longitudinal neuroimaging studies addressing the impact of antipsychotic drug treatment on brain changes in schizophrenia. A comprehensive search of PubMed was performed using combinations of key terms distributed into four blocks: “MRI”, “longitudinal”, “schizophrenia” and “antipsychotic”. Studies were considered to be eligible for the review if they were original articles. Studies that examined only changes in brain density were excluded. A total of 41 MRI studies were identified and reviewed. Longitudinal MRI studies did not provide a consistent notion of the effects of antipsychotic treatment on the pattern of brain changes over time in schizophrenia. Overall, most of the included articles did not find a linear relationship between the degree of exposure and progressive brain changes. Further short- and longterm studies are warranted to a better understanding of the influence of antipsychotics in brain structural changes in schizophrenia and also to verify whether first and second generation antipsychotics may differentially affect brain morphometry.
... Post-hoc studies showed that schizophrenia patients may have progressive ventricular dilation (Johnstone and Frith, 1996). Moreover, brain volume reductions and cortical and subcortical gray matter loss were also found in patients (Massana et al., 2005). All of these observations strongly suggest that neurodegeneration occurred during the pathogenesis of schizophrenia. ...
... Different atypical antipsychotics appear to exhibit specific effects on brain structure. Increases of GM in the caudate and nucleus accumbens, in the superior temporal gyrus (STG) and in the parietal as well as the occipital lobes have been described after treatment with risperidone (Massana et al., 2005;Molina et al., 2005;Girgis et al., 2006), and a decrease in the basal ganglia and an increase in the orbitofrontal cortex (OFC) and ACC after treatment with quetiapine (Stip et al., 2008(Stip et al., , 2009. However, even with the same compound, conflicting results emerged: olanzapine, for instance, has been reported to leave GM unaffected (Lieberman et al., 2005) but also to be associated with GM decrease in the frontal and parietal regions (Molina et al., 2007). ...
Schizophrenia is a severe, debilitating, chronic disease that is accompanied by morphologic changes within the brain. However, it is unclear to what extent alterations of grey and white matter in schizophrenia are linked to the disease itself, or whether they are a consequence of neuroleptic treatment. Typical and atypical antipsychotics exert differential effects on brain structure. Moreover, atypical antipsychotics may have distinct profiles with respect to grey matter in schizophrenic patients. Findings on drug-induced grey matter changes are heterogeneous due to variation in stage of illness, duration of treatment and use of multiple antipsychotics. Using voxel-based morphometry applied to high-resolution magnetic resonance images, we show that monotherapy with the atypical agent quetiapine (mean daily dose = 445 mg ± 200 s.d.) may induce structural brain changes in first-episode schizophrenia patients (N = 20) within 21 d of treatment. Specifically, we demonstrate longitudinal macroscopic changes (i.e. grey matter increases) in the left amygdalohippocampal region that were predicted by drug plasma levels but not daily doses. These structural alterations were accompanied by a clinical improvement of schizophrenic symptoms. Comparison with healthy controls (n = 30) showed that grey matter amount in the respective amygdalar region was significantly reduced in unmedicated first-episode schizophrenia patients. These findings suggest that drug-induced neuroplastic changes in schizophrenia can occur quickly and are dependent on pharmacokinetics.
... The systematic search yielded 1163 abstracts, of which 68 were initially selected for a full-text screening. One study, by Massana et al. [75], was excluded, as the stereotactic coordinates were not reported in the paper nor provided by the authors after request (personal communication). Another study, by Schaulfelberger et al. [76], was excluded because significant peak coordinates of structural brain changes were found only with small volume correction analysis. ...
Background: The results of multiple studies on the association between antipsychotic use and structural brain changes in schizophrenia have been assessed only in qualitative literature reviews to date. We aimed to perform a meta-analysis of voxel-based morphometry (VBM) studies on this association to quantitatively synthesize the findings of these studies.
Methods: A systematic computerized literature search was carried out through MEDLINE/PubMed, EMBASE, ISI Web of Science, SCOPUS and PsycINFO databases aiming to identify all VBM studies addressing this question and meeting predetermined inclusion criteria. All studies reporting coordinates representing foci of structural brain changes associated with antipsychotic use were meta-analyzed by using the activation likelihood estimation technique, currently the most sophisticated and best-validated tool for voxel-wise meta-analysis of neuroimaging studies.
Results: Ten studies (five cross-sectional and five longitudinal) met the inclusion criteria and comprised a total of 548 individuals (298 patients on antipsychotic drugs and 250 controls). Depending on the methodologies of the selected studies, the control groups included healthy subjects, drug-free patients, or the same patients evaluated repeatedly in longitudinal comparisons (i.e., serving as their own controls). A total of 102 foci associated with structural alterations were retrieved. The meta-analysis revealed seven clusters of areas with consistent structural brain changes in patients on antipsychotics compared to controls. The seven clusters included four areas of relative volumetric decrease in the left lateral temporal cortex [Brodmann area (BA) 20], left inferior frontal gyrus (BA 44), superior frontal gyrus extending to the left middle frontal gyrus (BA 6), and right rectal gyrus (BA 11), and three areas of relative volumetric increase in the left dorsal anterior cingulate cortex (BA 24), left ventral anterior cingulate cortex (BA 24) and right putamen.
Conclusions: Our results identify the specific brain regions where possible associations between antipsychotic drug usage and structural brain changes in schizophrenia patients are more consistently reported. Additional longitudinal VBM studies including larger and more homogeneous samples of schizophrenia patients may be needed to further disentangle such alterations from those possibly linked to the intrinsic pathological progressive process in schizophrenia.
Keywords: Schizophrenia; Antipsychotics; Voxel-based morphometry; Magnetic resonance imaging; Neuroimaging
... Although the initial descriptions of an increase in caudate nucleus volume were linked to long exposure to typical antipsychotics (Chakos et al. 1994;Keshavan et al. 1994), more recent investigations have also reported a volume increase in patients receiving atypical antipsychotics (i.e. clozapine or risperidone) (Staal et al. 2000;Massana et al. 2005). We did not find a statistically significant correlation between time on antipsychotic medication and volume of the caudate at the baseline scan (r = 0.03, p = 0.792). ...
Schizophrenia is a chronic brain disorder associated with structural brain abnormalities already present at the onset of the illness. Whether these brain abnormalities might progress over time is still under debate.
The aim of this study was to investigate likely progressive brain volume changes in schizophrenia during the first 3 years after initiating antipsychotic treatment. The study included 109 patients with a schizophrenia spectrum disorder and a control group of 76 healthy subjects. Subjects received detailed clinical and cognitive assessment and structural magnetic resonance imaging (MRI) at regular time points during a 3-year follow-up period. The effects of brain changes on cognitive and clinical variables were examined along with the impact of potential confounding factors.
Overall, patients and healthy controls exhibited a similar pattern of brain volume changes. However, patients showed a significant lower progressive decrease in the volume of the caudate nucleus than control subjects (F 1,307.2 = 2.12, p = 0.035), with healthy subjects showing a greater reduction than patients during the follow-up period. Clinical and cognitive outcomes were not associated with progressive brain volume changes during the early years of the illness.
Brain volume abnormalities that have been consistently observed at the onset of non-affective psychosis may not inevitably progress, at least over the first years of the illness. Taking together with clinical and cognitive longitudinal data, our findings, showing a lack of brain deterioration in a substantial number of individuals, suggest a less pessimistic and more reassuring perception of the illness.
... This mental disease is characterized by positive symptoms (hallucinations and delusional ideas), and negative and cognitive symptoms (low levels of emotional arousal, mental activity and social drive, decreased attention, memory and executive functions) (Sadock et al., 2009). Schizophrenia patients with progressive ventricular dilation (Johnstone and Frith, 1996), brain volume reductions, and cortical and subcortical gray matter loss (Massana et al., 2005) are identified by Post hoc studies, suggesting that neurodegeneration may occur during the pathogenesis of schizophrenia. ...
... Cross-sectional MRI studies suggest that treatment of schizophrenia with typical antipsychotic medications can be, but is not always, associated with enlarged caudate. Dose (Chakos et al. 1994) and treatment findings (Corson et al. 1999b;Keshavan et al. 1994;Lieberman et al. 2005;Massana et al. 2005) have been observed over periods of twelve to twenty-four months in longitudinal MRI studies. Treatment of schizophrenia with atypical antipsychotics for extended periods is associated with decreases in caudate volume (Corson et al. 1999b), although studies in rodents are not entirely consistent with the human data (Andersson et al. 2002;Lee et al. 1999). ...
Unlabelled:
Caudate and hippocampal volume differences in patients with schizophrenia are associated with disease and antipsychotic treatment, but local shape alterations have not been thoroughly examined. Schizophrenia patients randomly assigned to haloperidol and olanzapine treatment underwent magnetic resonance imaging (MRI) at 3, 6, and 12 months. The caudate and hippocampus were represented as medial representations (M-reps); mesh structures derived from automatic segmentations of high resolution MRIs. Two quantitative shape measures were examined: local width and local deformation. A novel nonparametric statistical method, adjusted exponentially tilted (ET) likelihood, was used to compare the shape measures across the three groups while controlling for covariates. Longitudinal shape change was not observed in the hippocampus or caudate when the treatment groups and controls were examined in a global analysis, nor when the three groups were examined individually. Both baseline and repeated measures analysis showed differences in local caudate and hippocampal size between patients and controls, while no consistent differences were shown between treatment groups. Regionally specific differences in local hippocampal and caudate shape are present in schizophrenic patients. Treatment-related related longitudinal shape change was not observed within the studied timeframe. Our results provide additional evidence for disrupted cortico-basal ganglia-thalamo-cortical circuits in schizophrenia.
Clinical trial information:
This longitudinal study was conducted from March 1, 1997 to July 31, 2001 at 14 academic medical centers (11 in the United States, one in Canada, one in the Netherlands, and one in England). This study was performed prior to the establishment of centralized registries of federally and privately supported clinical trials.
... Some clinical reports also suggest some atypical APDs may have a neuroprotective effect. A study of patients with first-episode schizophrenia reported that basal ganglia volume is increased in patients treated with risperidone (Massana et al, 2005). Treatment with risperidone increased the volume of gray matter in neuroleptic-naive patients (Molina et al, 2005). ...
Hypoglutamatergic function may contribute to cognitive impairment in schizophrenia (CIS). Subchronic treatment with the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), induces enduring deficits in novel object recognition (NOR) in rodents. Acute treatment with atypical antipsychotic drugs (APDs), which are serotonin (5-HT)(2A)/dopamine D(2) antagonists, but not typical APDs, eg, haloperidol, reverses the PCP-induced NOR deficit in rats. We have tested the ability of lurasidone, an atypical APD with potent 5-HT(1A) partial agonist properties, tandospirone, a selective 5-HT(1A) partial agonist, haloperidol, a D(2) antagonist, and pimavanserin, a 5-HT(2A) inverse agonist, to prevent the development of the PCP-induced NOR deficit. Rats were administered lurasidone (0.1 or 1 mg/kg), tandospirone (5 mg/kg), pimavanserin (3 mg/kg), or haloperidol (1 mg/kg) b.i.d. 30 min before PCP (2 mg/kg, b.i.d.) for 7 days (day1-7), followed by a 7-day washout (day 8-14). Subchronic treatment with PCP induced an enduring NOR deficit. Lurasidone (1 mg/kg) but not 0.1 mg/kg, which is effective to acutely reverse the deficit due to subchronic PCP, or tandospirone, but not pimavanserin or haloperidol, significantly prevented the PCP-induced NOR deficit on day 15. The ability of lurasidone co-treatment to prevent the PCP-induced NOR deficit was enduring and still present at day 22. The preventive effect of lurasidone was blocked by WAY100635, a selective 5-HT(1A) antagonists, further evidence for the importance of 5-HT(1A) receptor stimulation in the NOR deficit produced by subchronic PCP. Further study is needed to determine whether these results concerning mechanism and dosage can be the basis for prevention of the development of CIS in at risk populations.
... In the present study, when we removed four subjects who received conventional antipsychotics, the result was largely unchanged. This common effect of typical and atypical medication on basal ganglia volume is similar to that reported by Massana et al. (2005) after 3-months resperidione treatment and a significantly increased volume in the putamen was detected after 12 weeks of exposure to risperidone by Glenthoj et al. (2007). These studies agree that both conventional and atypical antipsychotic have effects on the basal ganglia in the early stage of treatment of schizophrenia. ...
Brain structure appears to alter after antipsychotic administration, but it is unknown whether these alterations are associated with improvement of psychopathology in patients with schizophrenia. In this study, the authors explore this relationship.
Altogether, 66 first-episode, drug-naive patients with schizophrenia and 23 well-matched healthy controls underwent brain magnetic resonance imaging scans at baseline. All 23 healthy controls and 42 of the patients were rescanned after 6 weeks follow-up. The patients received regular antipsychotic treatment during the 6-week period and their psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and 6 weeks. The difference in PANSS scores between baseline and 6 weeks was expressed as a ratio of the scores at baseline - 'PANSS reduction ratio'. A modified tensor-based morphometry procedure was applied to analyse longitudinal images. Correlations between regional volume changes, PANSS reduction ratio and antipsychotic drug dosages were explored.
Compared with healthy controls, there was a significant increase in grey-matter volume of the right putamen in patients after 6 weeks treatment. This volume change was positively correlated with a positive PANSS reduction score but not related to drug dosages.
Putaminal volume increased after 6 weeks antipsychotic treatment in first-episode schizophrenia. The increased volume was closely correlated with improved psychopathology, suggesting the putamen might be a biomarker to predict the treatment response in schizophrenia.
... A recent systematic review of 33 articles found that typical antipsychotic exposure, even for a short duration (b12 weeks), was associated with increased basal ganglial volumes (Navari and Dazzan, 2009). Exposure to atypicals did not have a consistent association with basal ganglial volumes, with one study finding increased volumes (Massana et al., 2005), while several other studies finding unchanged or decreased volumes (Heitmiller et al., 2004;Navari and Dazzan, 2009). ...
The most prevalent comorbid disorder in pediatric bipolar disorder (BD) is attention-deficit/hyperactivity disorder (ADHD). As caudate volume abnormalities have been demonstrated in both BD and ADHD, this study sought to determine whether these findings could be attributed to separable effects from either diagnosis. High resolution anatomical magnetic resonance (MRI) images were obtained from youth in 4 groups: BD with comorbid ADHD (n=17), BD without comorbid ADHD (n=12), youth with ADHD alone (n=11), and healthy control subjects (n=24). Caudate, putamen, and globus pallidus volumes were manually traced for each subject using BrainImageJava software by a reliable rater blinded to diagnosis. There was a significant effect of diagnosis on striatal volumes, with ADHD associated with decreased caudate and putamen volumes, and BD associated with increased caudate, putamen, and globus pallidus volumes. Thus, the presence or absence of comorbid ADHD in patients with BD was associated with distinct alterations in caudate volumes, suggesting that these groups have different, but related, mechanisms of neuropathology.
... Dose-dependent volumetric effects of quetiapine have not previously been described. Interestingly, clinical studies with risperidone have associated striatal volume increases with high doses of risperidone (6.05 mg/d) (Massana et al. 2005), whereas moderate (3.64 mg/d) (Glenthoj et al. 2007) and low (2.7 mg/d) (Lang et al. 2001) risperidone doses caused marginal increases or no striatal volume changes, respectively. According to a hypothesis put forward by Kapur & Seeman (2001), a transiently high striatal D 2 blockade may drive the antipsychotic effect in SGAs. ...
First-generation antipsychotics have been associated with striatal volume increases. The effects of second-generation antipsychotics (SGAs) on the striatum are unclear. Moreover, SGAs may have neuroprotective effects on the hippocampus. Dose-dependent volumetric effects of individual SGAs have scarcely been investigated. Here we investigated structural brain changes in antipsychotic-naive, first-episode schizophrenia patients after 6 months treatment with the SGA, quetiapine. We have recently reported on baseline volume reductions in the caudate nucleus and hippocampus. Baseline and follow-up T1-weighted images (3 T) from 22 patients and 28 matched healthy controls were analysed using tensor-based morphometry. Non-parametric voxel-wise group comparisons were performed. Small volume correction was employed for striatum, hippocampus and ventricles. Dose-dependent medication effects and associations with psychopathology were assessed. Patients had significant bilateral striatal and hippocampal loss over the 6-month treatment period. When compared to controls the striatal volume loss was most pronounced with low quetiapine doses and less apparent with high doses. Post-hoc analyses revealed that the striatal volume loss was most pronounced in the caudate and putamen, but not in accumbens. Conversely, hippocampal volume loss appeared more pronounced with high quetiapine doses than with low doses. Clinically, higher baseline positive symptoms were associated with more striatal and hippocampal loss over time. Although patients' ventricles did not change significantly, ventricular increases correlated with less improvement of negative symptoms. Progressive regional volume loss in quetiapine-treated, first-episode schizophrenia patients may be dose-dependent and clinically relevant. The mechanisms underlying progressive brain changes, specific antipsychotic compounds and clinical symptoms warrant further research.
... However, their atypical APD groups were treated with a number of different drugs making comparison with previous studies difficult. Massana et al. (2005) found that drug-naïve patients treated with the atypical APD resperidone exhibited an increase in striatal volume; however, this effect was seen at higher doses of resperidone and may reflect an action more like that of typical APDs. These findings suggest that typical APDs and risperidone may act on the striatum; the atypical APDs clozapine and olanzapine may have little effect on the striatum. ...
Antipsychotic drugs (APDs) have been classified as typical or atypical based on their liability to produce extrapyramidal side effects: atypical APDs are less likely to produce extrapyamidal side effects at therapeutic doses. Evidence from immediate early gene immunohistochemical, electrophysiological, microdialysis, imaging, and behavioral studies suggests that typical APDs preferentially affect the nucleus accumbens (NAc) and the dorsal striatum while atypical APDs preferentially affect the NAc and medial prefrontal cortex (PFC). We review some of this evidence and then discuss studies that have employed cognitive tasks shown previously to depend on dorsal striatal or medial PFC function in schizophrenic patients treated with typical or atypical APDs. Results revealed that patients treated with typical APDs displayed deficits in cognitive tasks that depended on the dorsal striatum but not in tasks that depended on the medial PFC and that those treated with atypical APDs displayed deficits in cognitive tasks that depended on the medial PFC but not in cognitive tasks that depended on the dorsal striatum. These findings suggest that some of the cognitive deficits seen in schizophrenic patients may be related to the medications that are used to treat them.
... Impairments in subcortical-cortical and cortical-cortical connectivity likely contribute to the cognitive, perceptual, and motor difficulties associated with schizophrenia. Antipsychotic medications can affect both subcortical and cortical grey and white matter volumes (Lang et al., 2004;Kopelman et al., 2005;Lieberman et al., 2005;Massana et al., 2005;Khorram et al., 2006). However, the possible effects of antipsychotic medication on specific white matter fibre tracts connecting cortical and subcortical regions are uncertain. ...
Abnormalities in connectivity are thought to contribute to the symptoms of schizophrenia. Accumulating evidence suggests that antipsychotic medication affects both subcortical and cortical grey and white matter volumes. The goal of this study was to investigate the effects of antipsychotic medication on two white matter tracts: a subcortical-cortical tract, the anterior and posterior limbs of the internal capsule; and a cortical-cortical tract, the corpus callosum. Magnetic resonance imaging was conducted on 10 chronic schizophrenia patients treated with typical antipsychotics and 20 healthy controls at baseline. Patients were switched to olanzapine and both groups were rescanned after 1 year. At baseline, the volume of the anterior limb of the internal capsule was 24% smaller in typical-treated patients than controls (p = 0.009). Patients treated with greater amounts of chlorpromazine-equivalent daily dosage had smaller anterior internal capsule volumes at baseline (r = -0.65, p = 0.04). At follow-up, after being switched to olanzapine, there were no significant differences between patients and controls. Patients with schizophrenia had a significant 25% increase in anterior internal capsule volume from baseline to follow-up compared with controls (p = 0.04). These effects were most prominent in the anterior limb of the internal capsule, which consists of fronto-thalamic pathways, and were not statistically significant in the posterior limb of the internal capsule or corpus callosum. Olanzapine may be effective in normalizing fronto-thalamic structural connectivity in schizophrenia.
>>> PUBLISHDED ON NEUROIMAGE 10.1016/j.neuroimage.2020.117220 ------ RESEARCHGATE PAGE https://www.researchgate.net/publication/343526352_A_meta-analytic_approach_to_mapping_co-occurent_grey_matter_volume_increases_and_decreases_in_psychiatric_disorders <<< Numerous studies have investigated gray matter (GM) volume changes in diverse patient groups. Reports of disorder-related GM reductions are common in such work, but many studies also report evidence for GM volume increases in patients. It is unclear whether these GM increases and decreases independent or related in some way. Here, we address this question using a novel meta-analytic network mapping approach. We used a coordinate-based meta-analysis of 64 voxel-based morphometry studies of psychiatric disorders to calculate the probability of finding a GM increase or decrease in one region given an observed change in the opposite direction in another region. Estimating this co-occurrence probability for every pair of brain regions allowed us to build a network of concurrent GM changes of opposing polarity. Our analysis revealed that disorder-related GM increases and decreases are not independent; instead, a GM change in one area is often statistically related to a change of opposite polarity in other areas, highlighting distributed yet coordinated changes in GM volume as a function of brain pathology. Most regions showing GM changes linked to an opposite change in a distal area were located in salience, executive-control and default mode networks, as well as the thalamus and basal ganglia. Moreover, pairs of regions showing coupled changes of opposite polarity were more likely to belong to different canonical networks than to the same one. Our results suggest that regional GM alterations in psychiatric disorders are often accompanied by opposing changes in distal regions that belong to distinct functional networks.
Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.
Background:
Studies of pre-and post-treatment striatal volume in schizophrenia have reported conflicting results.
Materials and methods:
We assessed dorsal striatal (caudate and putamen) volumes bilaterally in 22 never-treated, non-substance-abusing patients with first-episode schizophrenia or schizophreniform disorder and 23 healthy controls matched for age, sex and educational status. Patients received either risperidone or flupenthixol long acting injection and were compared by structural MRI with controls at weeks 0, 4 and 13. T1-weighted data on a 3T MRI scanner were obtained and images were reconstructed using FreeSurfer. Treatment outcome was assessed by changes in psychopathology, insight, functionality, cognitive performance and motor symptoms.
Results:
Caudate, but not putamen volumes was significantly larger in patients bilaterally at baseline (P=0.01). Linear mixed effects repeated measures found no significant group × time interactions for any of the regions. Caudate volume was not significantly associated with improvements in psychotic symptoms. Also, the findings of a regression model were inconsistent insofar as larger caudate volume was associated with less improvement in depression scores, greater improvement in functionality and greater improvement in verbal learning but less improvement in reasoning and problem solving (left caudate) and composite cognitive score (right caudate).
Conclusions:
The increased caudate volumes prior to treatment are contrary to previous reports in never-treated patients with first-episode schizophrenia, and together with our failure to demonstrate volume changes related to acute treatment, call into question previous proposals that enlarged caudate volume is a consequence of antipsychotic treatment.
Despite a large number of neuroimaging studies in schizophrenia reporting subtle brain abnormalities, we do not know to what extent such abnormalities reflect the effects of antipsychotic treatment on brain structure. We therefore systematically reviewed cross-sectional and follow-up structural brain imaging studies of patients with schizophrenia treated with antipsychotics. 30 magnetic resonance imaging (MRI) studies were identified, 24 of them being longitudinal and six cross-sectional structural imaging studies. In patients with schizophrenia treated with antipsychotics, reduced gray matter volume was described, particularly in the frontal and temporal lobes. Structural neuroimaging studies indicate that treatment with typical as well as atypical antipsychotics may affect regional gray matter (GM) volume. In particular, typical antipsychotics led to increased gray matter volume of the basal ganglia, while atypical antipsychotics reversed this effect after switching. Atypical antipsychotics, however, seem to have no effect on basal ganglia structure.
How to cite this article: E. Zampieri, M. Bellani, B. Crespo-Facorro and P. Brambilla Basal ganglia anatomy and schizophrenia: the role of antipsychotic treatment. Epidemiology and Psychiatric Sciences, Available on CJO 2014 This Section of Epidemiology and Psychiatric Sciences regularly appears in each issue of the Journal to stress the relevance of epidemiology for behavioral neurosciences, reporting the results of studies that explore the use of an epidemiological approach for providing a better understanding of the neural basis of major psychiatric disorders and, in turn, the utilisation of the behavioural neurosciences for promoting innovative epidemiological research. The final scope is to help the translation of most relevant research findings into everyday clinical practice. These contributions are written in house by the journal's editorial team or commissioned by the Section Editor (no more than 1000 words, short unstructured abstract, 4 keywords , one Table or Figure and up to ten references). Paolo Brambilla, Section Editor
The genetic contribution to schizophrenia etiopathogenesis is underscored by the fact that the best predictor of developing schizophrenia is having an affected first-degree relative, which increases lifetime risk by tenfold, as well as the observation that when both parents are affected, the risk of schizophrenia increases to approximately 50%, compared with 1% in the general population. The search to elucidate the complex genetic architecture of schizophrenia has employed various approaches, including twin and family studies to examine co-aggregation of brain abnormalities, studies on genetic linkage and studies using genome-wide association to identify genetic variations associated with schizophrenia. 'Endophenotypes, or 'intermediate phenotypes, are potentially narrower constructs of genetic risk. Hypothetically, they are intermediate in the pathway between genetic variation and clinical phenotypes and can supposedly be implemented to assist in the identification of genetic diathesis for schizophrenia and, possibly, in redefining clinical phenomenology.
Progressive enlargement of basal ganglia volume has been observed in schizophrenia individuals, potentially being sustained by chronic administration of antipsychotic drugs. Here we briefly summarise the state of the art of the role of antipsychotic in leading to increased basal ganglia in schizophrenia, particularly focusing on the caudate nucleus.
At the beginning of the twentieth century, many authors proposed that a considerable number of schizophrenic patients experience genuine motor abnormalities (GMA). In the era of antipsychotic treatment, GMA became a scientifically and clinically challenging characteristic of schizophrenia. Over the past 10 years, several magnetic resonance imaging (MRI) studies suggested a crucial role of the motor system in this disorder. Constituting a major relay center in the extrapyramidal motor system and being involved in the automatic execution of motor plans, an involvement of the basal ganglia with GMA and schizophrenia is plausible. However, the precise morphological correlates of GMA have remained controversial. The aim of this paper is to systematically review structural neuroimaging findings on GMA and basal ganglia in individuals with schizophrenia. Nineteen structural MRI studies were identified for inclusion in the review. Considering the extant data, there is some evidence for volumetric and shape alterations of basal ganglia in schizophrenia being in part determined by psychopathology and GMA, and not entirely explained by antipsychotic medication effects.
Abnormal brain structure of frontal and temporal brain regions has been suggested to occur in patients with schizophrenia who have frequent auditory verbal hallucinations (AVH). However, it is unknown whether this is specific to this patient subgroup. This study tested the hypothesis that frontotemporal gray matter volume changes would characterize patients with persistent AVH (pAVH) in contrast to healthy controls and patients without AVH. Using structural magnetic resonance imaging at 3T, we studied 20 patients with schizophrenia and 14 matched healthy controls. Ten patients were classified as having chronic and treatment resistant AVH, whereas the remaining 10 patients either never had AVH in the past or were in full remission with regard to AVH (nAVH). Using a multivariate statistical technique for structural data, i.e. "source-based morphometry" (SBM), we investigated naturally grouping patterns of gray matter volume variation among individuals, the magnitude of their expression between-groups and the relationship between gray matter volume and AVH-specific measures. SBM identified a reduction of medial and inferior frontal, insular and bilateral temporal gray matter volume between pAVH and nAVH. This pattern did not differ between nAVH patients and controls and was associated with "physical" AVH characteristics (such as symptom duration, location, frequency and intensity) in the pAVH patient group. These results suggest that a pattern of lower gray matter volume in medial frontal and bilateral temporal cortical regions differentiates between patients with persistent AVH and non-hallucinating patients. Moreover, the data support a specific role of this neural pattern in AVH symptom expression.
Executive function impairments are a core feature of bipolar I disorder (BD-I), not only present during acute episodes but also persisting following remission of mood symptoms. Despite advances in knowledge regarding the neural basis of executive functions in healthy subjects, research into morphological abnormalities underlying the deficits in BD-I is lacking.
Patients with BD-I within three months of sustained remission from their first manic episode (n = 41) underwent neuropsychological testing and a 3T magnetic resonance imaging scan and were compared to healthy subjects matched for age, sex, and premorbid IQ (n = 30). Group dorsolateral prefrontal cortex (DLPFC; Brodmann areas 9 and 46) and caudate volumes were examined and analyzed for relationships with the average score from three computerized tests of executive function: Spatial Working Memory, Stockings of Cambridge, and Intradimensional/Extradimensional Shift.
Right caudate volumes were enlarged in patients (z = 3.57, p < 0.05 corrected). No differences in DLPFC volumes were found. Patients showed large deficits in executive function relative to healthy subjects (d = -0.92, p < 0.001). While in healthy subjects, a larger right (r = +0.39, p < 0.05) and left (r = +0.44, p < 0.05) caudate was associated with better executive function score, in patients, larger right (r = -0.36, p < 0.05) and left (r = -0.34, p < 0.05) volumes correlated with poorer performance.
Although the etiology of gray matter changes is unknown, volume increases in the right caudate may be an important factor underlying executive function impairments during remission in patients with BD-I.
Little is known about the neural basis of delusional infestation (DI), the delusional belief to be infested with pathogens. Case series and the response to anti-dopaminergic medication indicate disruptions in dopaminergic neurotransmission in the striatum (caudate, putamen), but did not allow for population-based inference. Here, we report the first whole-brain structural neuroimaging study to investigate gray and white matter abnormalities in DI compared to controls. In this study, we used structural magnetic resonance imaging and voxel-based morphometry to investigate gray and white matter volume in 16 DI patients and 16 matched healthy controls. Lower gray matter volume in DI patients compared to controls was found in left medial, lateral and right superior frontal cortices, left anterior cingulate cortex, bilateral insula, left thalamus, right striatal areas and in lateral and medial temporal cortical regions (p<0.05, cluster-corrected). Higher white matter volume in DI patients compared to controls was found in right middle cingulate, left frontal opercular and bilateral striatal regions (p<0.05, cluster-corrected). This study shows that structural changes in prefrontal, temporal, insular, cingulate and striatal brain regions are associated with DI, supporting a neurobiological model of disrupted prefrontal control over somato-sensory representations.
Context:
Antipsychotic treatment is the first-line treatment option for schizophrenia. Individual studies suggested they can significantly affect brain structure and account for progressive brain changes observed during the illness.
Objectives:
To quantitatively examine the effect of antipsychotics as compared to illness related factors on progressive brain changes in schizophrenia.
Data sources:
Electronic databases were searched until April 2012. All magnetic resonance imaging studies reporting progressive brain changes in schizophrenia subjects and antipsychotic exposure were retrieved.
Study selection:
30 longitudinal MRI studies with antipsychotic administration in schizophrenia patients met the inclusion criteria.
Data extraction:
Brain volumes before and after antipsychotic exposure, duration of illness, severity of psychotic symptoms as well as demographic, clinical, and methodological variables were extracted from each publication, or obtained directly from its authors.
Data synthesis:
The overall sample was of 1046 schizophrenia patients and 780 controls for a median duration of follow-up of 72.4 weeks. At baseline, patients showed significant whole brain volume reductions and enlarged lateral ventricle (LV) volumes compared to controls. No baseline volumetric abnormalities were detected in the gray matter volumes (GMV), white matter volumes, cerebrospinal fluid and caudate nucleus. Longitudinally, there were progressive GMV decreases and LV enlargements in patients but not in controls. The GMV decreases were inversely correlated with cumulative exposure to antipsychotic treatments, while no effects were observed for duration of illness or illness severity.
Conclusions:
Schizophrenia is characterized by progressive gray matter volume decreases and lateral ventricular volume increases. Some of these neuroanatomical alterations may be associated with antipsychotic treatment.
Although neurotransmitter-based hypotheses still prevail current thinking about the mechanism of action of psychotropic drugs, recent insight into the pathophysiology of psychiatric disorders has unveiled a range of new therapeutic actions of the drugs used to treat those disorders. Especially antidepressants seem to exert at least some of their effects via restoration of synaptic/neuronal plasticity. In addition, there is increasing evidence that several of the second-generation antipsychotics and some anticonvulsants affect neuronal survival/apoptosis as well as synaptic plasticity. Most of this evidence stems from work in animals. In this review, we will focus on the evidence for neuroplastic effects of psychotropic drugs in humans being aware of the fact that most of the data are derived from animals and that volumetric studies in humans can only indicate structural plasticity and not necessarily functional plasticity. However, as the data from human studies are rather poor and inconclusive, and sometimes even conflicting, it seems impossible to draw genereal conclusions. Until now studies on neuroplasticity in humans can only explain small pieces of the effects of pschotropic drugs on brain plasticity in humans. Nevertheless, future prospects for the development of new drugs targeting brain plasticity will be of importance and will complete this overview.
Exposure to antipsychotic medication has been extensively associated with structural brain changes in the basal ganglia (BG). Traditionally antipsychotics have been divided into first and second generation antipsychotics (FGAs and SGAs) however, the validity of this classification has become increasingly controversial. To address if specific antipsychotics induce differential effects on BG volumes or whether volumetric effects are explained by FGA or SGA classification, we reviewed longitudinal structural magnetic resonance imaging (MRI) studies investigating effects of antipsychotic monotherapy. Material and Methods:We systematically searched PubMed for longitudinal MRI studies of patients with schizophrenia or non-affective psychosis who had undergone a period of antipsychotic monotherapy. We used specific, predefined search terms and extracted studies were hand searched for additional studies. Results:We identified 13 studies published in the period from 1996 to 2011. Overall six compounds (two classified as FGAs and four as SGAs) have been investigated: haloperidol, zuclophentixol, risperidone, olanzapine, clozapine, and quetiapine. The follow-up period ranged from 3-24 months. Unexpectedly, no studies found that specific FGAs induce significant BG volume increases. Conversely, both volumetric increases and decreases in the BG have been associated with SGA monotherapy. Discussion:Induction of striatal volume increases is not a specific feature of FGAs. Except for clozapine treatment in chronic patients, volume reductions are not restricted to specific SGAs. The current review adds brain structural support to the notion that antipsychotics should no longer be classified as either FGAs or SGAs. Future clinical MRI studies should strive to elucidate effects of specific antipsychotic drugs.
Sub-chronic administration of phencyclidine to the rat induces enduring cognitive and pathophysiological changes that resemble some features of schizophrenia. The present study aimed to determine if concurrent administration of the atypical antipsychotic, risperidone, could attenuate the effect of phencyclidine on object recognition memory and parvalbumin-containing neurons in the prefrontal cortex. Rats were administered phencyclidine at a dose of 2 mg/kg i.p. bi-daily for 1 week, or vehicle. Half of the phencyclidine group was concurrently treated with risperidone (0.5 mg/kg i.p.) twice daily for 10 days, beginning 3 days before the start of phencyclidine administration. Novel object recognition memory and subsequent brain analysis were assessed 6 weeks post-phencyclidine treatment. Phencyclidine produced a deficit in object recognition memory as measured by the discrimination ratio. In addition, 6 weeks post-phencyclidine, analysis of brains showed a reduction in expression of parvalbumin-immunoreactive neurons in the prefrontal cortex, with specific deficits observed in the prelimbic region, but not infralimbic or cingulate cortices. Concurrent administration of risperidone showed no protective effects against these deficits. These results show the importance of the sub-chronic phencyclidine rat in modelling cognitive and prefrontal pathophysiology observed in schizophrenia, but suggest that concurrent risperidone is not neuroprotective in this model.
Automated methods to delineate brain structures of interest are required to analyze large amounts of imaging data like that being collected in several on going multi-center studies. We have previously reported on using artificial neural networks (ANN) to define subcortical brain structures such as the thalamus (0.825), caudate (0.745), and putamen (0.755). One of the inputs into the ANN is the apriori probability of a structure existing at a given location. In this previous work, the apriori probability information was generated in Talairach space using a piecewise linear registration. In this work we have increased the dimensionality of this registration using Thirion's demons registration algorithm. The input vector consisted of apriori probability, spherical coordinates, and an iris of surrounding signal intensity values. The output of the neural network determined if the voxel was defined as one of the N regions used for training. Training was per-formed using a standard back propagation algorithm. The ANN was trained on a set of 15 images for 750,000,000 iterations. The resulting ANN weights were then applied to 6 test images not part of the training set. Relative overlap calculated for each structure was 0.875 for the thalamus, 0.845 for the caudate, and 0.814 for the putamen. With the modifications on the neural net algorithm and the use of multi-dimensional registration, we found substantial improvement in the automated segmentation method. The resulting segmented structures are as reliable as manual raters and the output of the neural network can be used without additional rater intervention.
Minor motor and sensory deficits or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. The thalamus and basal ganglia are accepted as being important for both motor control and integration of sensory input. However, whether NSS are related to alterations of these brain regions remains controversial.
Twenty patients with recent onset schizophrenia were investigated using high-resolution magnetic resonance imaging (MRI) at 3 Tesla. NSS were examined on the Heidelberg Scale after remission of acute symptoms and related to both volumetric and shape measurements of thalamus, caudate nucleus, putamen, and globus pallidus, respectively. Age, education, medication and duration of illness were considered as potential confounders.
NSS were associated with structural alterations predominantly in the thalamus, the left caudate nucleus, and in the right globus pallidus. According to shape analyses these associations referred to regionally specific morphometric alterations rather than to global atrophy of the respective structures.
Our findings provide new insights into the association of NSS with brain morphometric alterations and lend further support to an involvement of multiple subcortical regions in schizophrenia.
An accumulating body of evidence point to the significance of neuroinflammation and immunogenetics also in schizophrenia. Recent genome-wide studies in schizophrenia suggest immune involvement in schizophrenia. Microglia are the resident macrophage of the brain and major players in innate immunity in the CNS. They respond rapidly to even minor pathological changes in the brain and may contribute directly to the neuronal degeneration by producing various pro-inflammatory cytokines and free radicals. In many aspects, the neuropathology of schizophrenia is closely associated with microglial activation. We and other researchers have shown the inhibitory effects of some typical or atypical antipsychotics on the release of inflammatory cytokines and free radicals from activated microglia, both of which are not only directly toxic to neurons but also cause a decrease in neurogenesis as well as white matter abnormalities in the brains of the patients with schizophrenia. The treatment through the inhibition of microglial activation may shed new light on the therapeutic strategy of schizophrenia.
Introduction:
Abnormalities of the P300 event related potential (ERP) and of hippocampal structure are observed in individuals with psychotic disorders and their unaffected relatives. The understanding and clinical management of psychotic disorders are largely based on the descriptive Kraepelinian distinction between 'dementia praecox' and 'manic depressive psychosis', and not dependant on any well demarcated biological underpinnings. The hippocampus is postulated to be one of the main P300 generators, yet it remains unknown whether hippocampal volume decrements are associated with P300 deficits in psychosis, and whether any association is shared across non-affective and affective psychotic disorders.
Methods:
228 subjects from the Maudsley Family Psychosis Study comprising 55 patients with non-affective psychosis, 23 patients with psychotic bipolar disorder, 98 unaffected relatives, and 52 unrelated controls contributed structural MRI and ERP data. To study the relationship between hippocampal volume and P300 ERP, a seemingly unrelated regression methodology was used, accounting for whole brain volumes, clinical groups, age and gender in the analysis.
Results:
An association between left hippocampal volume and P300 latency in the combined sample comprising non-affective and affective psychotic patients, their relatives and controls was observed. There was an inverse relationship between brain structure and function in that prolongation of P300 latencies was associated with smaller left hippocampal volumes. On subdividing the sample based on Kraepelinian dichotomy, this association remained significant only for the non-affective psychosis group, comprising patients and their unaffected relatives.
Conclusions:
Based on our findings, P300 latency, a measure of the speed of neural transmission, appears to be related to the size of the left hippocampus in schizophrenia, but not in psychotic bipolar disorder. It seems that underlying neuro-biological characteristics could help in unravelling the traditional Kraepelinian differentiation between the two major psychoses. The specificity of this brain structure-function association for schizophrenia opens the scope for further research using integration of multimodal biological data for objective categorisation of psychosis.
The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients. Sixteen remitted, stable patients with first-episode schizophrenia, schizoaffective or schizophreniform disorder and 20 healthy controls were included. Two magnetic resonance imaging brain scans were obtained from all subjects with a 1-year interval. The patients either discontinued (n = 8) their atypical antipsychotic medication (olanzapine, risperidone, or quetiapine) or did not (n = 8) discontinue during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens, and putamen were obtained. Multiple linear regression analyses were used to assess main effects for group (patient-control) and discontinuation (yes-no) for brain volume (change) while correcting for age, sex, and intracranial volume. Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls. Our data suggest decreases in the nucleus accumbens and putamen volumes during the interval in patients who discontinued antipsychotic medication, whereas increases were found in patients who continued their antipsychotics. We confirmed earlier findings of excessive gray matter volume decrements in patients with schizophrenia compared with normal controls. We found evidence suggestive of decreasing volumes of the putamen and nucleus accumbens over time after discontinuation of medication. This might suggest that discontinuation reverses effects of atypical medication.
There is increasing evidence that antipsychotic (APD) may affect brain structure directly. To examine this, we developed a rodent model that uses clinically relevant doses and serial magnetic resonance imaging (MRI), followed by postmortem histopathological analysis to study the effects of APD on brain structures.
Antipsychotic , haloperidol, and olanzapine were continuously administered to rats via osmotic minipumps to maintain clinic-like steady state levels for 8 weeks. Longitudinal in vivo MRI scanning (T₂-weighted) was carried out at baseline, 4 weeks, and 8 weeks, after which animals were perfused and their brains preserved for ex vivo MRI scanning. Region of interest analyses were performed on magnetic resonance images (both in vivo as well as ex vivo) along with postmortem stereology using the Cavalieri estimator probe.
Chronic (8 weeks) exposure to both haloperidol and olanzapine resulted in significant decreases in whole-brain volume (6% to 8%) compared with vehicle-treated control subjects, driven mainly by a decrease in frontal cerebral cortex volume (8% to 12%). Hippocampal, corpus striatum, lateral ventricles, and corpus callosum volumes were not significantly different from control subjects, suggesting a differential effect of APD on the cortex. These results were corroborated by ex vivo MRI scans and decreased cortical volume was confirmed postmortem by stereology.
This is the first systematic whole-brain MRI study of the effects of APD, which highlights significant effects on the cortex. Although caution needs to be exerted when extrapolating results from animals to patients, the approach provides a tractable method for linking in vivo MRI findings to their histopathological origins.
Seit den 80er Jahren des letzten Jahrhunderts gibt es zahlreiche Nachweise, dass NSS bei psychotischen Patienten besonders stark ausgeprägt sind. Dank der Entwicklung moderner Bildgebungsverfahren wurde es möglich, Zusammenhänge zwischen NSS und Hirnveränderungen zu untersuchen. Dabei waren die Analysen zunächst auf a priori definierte Hirnareale beschränkt. Mit der optimierten voxel-basierten Morphometrie (VBM) steht inzwischen eine Methode zur Verfügung, die eine standardisierte strukturelle Analyse des gesamten Hirns ermöglicht. Allerdings gibt es bisher nur wenige Studien, die entsprechende strukturelle Zusammenhänge mit Hilfe der optimierten VBM untersuchten. Darüber hinaus weisen diese Studien zum Teil methodische Einschränkungen auf. So wurden zum Beispiel Kleinhirn und WM teilweise nicht mit einbezogen oder der Stichprobenumfang war relativ gering. Zudem wurden bisher keine Analysen der NSS-Einzelitems durchgeführt. Mit Hilfe der vorliegenden Untersuchung wurde versucht, die bisherigen Einschränkungen zu überwinden und bestehende Lücken zu schließen. An einer Stichprobe von 102 Patienten mit einer psychotischen Ersterkrankung wurden mit Hilfe optimierter VBM-Analysen Zusammenhänge zwischen der Ausprägung von NSS und strukturellen Hirnveränderungen untersucht. Als Grundlage diente hierbei die Heidelberger NSS-Skala. Die optimierten VBM-Analysen wurden für den NSS-Gesamtwert, die HNS-Subskalen sowie die HNS-Einzelitems durchgeführt. Dabei konnten lediglich für die beiden motorischen Subskalen motorische Koordination und komplexe Bewegungen morphologische zerebrale und zerebellare Korrelate nachgewiesen werden. Auch bezüglich der Einzelitems ergaben die optimierten VBM-Analysen in erster Linie signifikante Zusammenhänge zwischen hohen Itemwerten und verringerter Volumina der GM und WM bei den motorischen Items. Mit Ausnahme der Diadochokinese konnten für nahezu alle Items der Skala motorische Koordination strukturelle Veränderungen in relevanten Arealen nachgewiesen werden. Dies spricht für die Validität dieser HNS-Skala. Insgesamt stehen die Ergebnisse in Einklang mit bisherigen Befunden. Es zeigten sich signifikante Assoziationen zwischen der Ausprägung von NSS und verminderten Volumina kortikaler, subkortikaler und zerebellarer Strukturen, welche für die Motorik und sensorische Verarbeitung eine entscheidende Rolle spielen. Im Hinblick auf die beteiligten Strukturen stützen die vorliegenden Ergebnisse das Modell der kognitiven Dysmetrie, welches davon ausgeht, dass der Symptomatik einer Schizophrenie ein gestörter kortikal-subkortikal-zerebellarer Kreislauf zugrunde liegt. Darüber hinaus sind NSS neben beeinträchtigter Netzwerke oder Kreisläufe aufgrund der vorliegenden Ergebnisse auch auf strukturelle Veränderungen diskreter, aufgabenspezifischer Areale zurückzuführen. Weiter liefern die Analysen einen Hinweis dafür, dass besonders die motorischen NSS mit strukturellen Hirnveränderungen in Verbindung stehen, welche auch die psychopathologische Symptomatik bedingen. Motorische NSS und Symptome einer schizophrenen Psychose scheinen somit auf einer Beeinträchtigung gemeinsamer Hirnstrukturen zu basieren. Vor diesem Hintergrund ist es vorstellbar, dass NSS eine eigenständige Symptomgruppe psychotischer Erkrankungen bilden und NSS-Skalen zukünftig bisherige diagnostische Verfahren ergänzen. Since the nineteen-eighties numerous studies support the pronounced occurrence of NSS in psychotic patients. Due to the development of modern imaging techniques it was possible to investigate associations between NSS and structural brain changes. Initially, analyses were restricted to predefined discrete brain areas. Meanwhile, optimized voxel-based morphometry (VBM) makes standardized structural whole brain analyses possible. However, until now there are only few studies which investigated structural associations by using VBM. Furthermore, there are some methodological restrictions in these studies like small sample sizes or a partly missing involvement of the cerebellum or white matter. The aim of this study was to overcome these limitations and to close existing gaps. In a sample of 102 patients with first-episode psychosis associations between NSS and structural brain alterations were analyzed by using optimized voxel-based morphometry. NSS were assessed on the Heidelberg NSS Scale (HNS). VBM-analyses included the HNS total score, HNS subscales as well as HNS items. Only the motor subscales motor coordination and complex motor tasks showed significant morphological cerebral and cerebellar correlates. Similar results were found for the analyses of the HNS-items. Mainly the motor items showed significant correlations between increased scores and decreased gray and white matter volume. With the exception of diadochokinesis all items of the motor coordination subscale are associated with structural alterations in relevant brain areas. This fact supports the structural validity of the subscale. Overall, the results are in line with previously reported findings. There are significant associations between increased NSS scores and decreased volumes of cortical, subcortical and cerebellar structures, which are important for motor and sensory integration and processing. With regard to the involved structures, the findings support the model of cognitive dysmetria which hypothesizes changes in a cortico-cerebellar-thalamic-cortical circuit to underlie schizophrenia. Moreover, the results reveal that NSS are also due to structural changes in discrete task specific areas. Especially the motor signs are associated with structural changes in areas which account for psychopathological symptoms. Against this background, it is imaginable that in future, NSS could serve as an independent group of psychotic symptoms and NSS-scales could extent hitherto existing diagnostic methods.
Recent neuroimaging studies have revealed progressive morphological brain changes during the course of schizophrenia, and the neurotrophic and neurogenetic effects of atypical antipsychotics are believed to prevent or retard these brain volume reductions. In addition to drug-induced neural stem cell (NSC) activation, transplantation of exogenous NSCs has been proposed as a possible approach to repair the damaged brain in psychiatric disease. NSC transplantation embraces not only neuron replacement but also enhanced neuroprotection of existing neurons with the goal of restoring the impaired brain. However, little is known about the cell-cell interactions of exogenous NSCs with existing neurons, or about their neuroprotective actions especially in psychiatric diseases. In the present study, we used cortical neuron cultures to examine the neurotrophism and neuroprotection of exogenous NSCs against the neuronal damage induced by exposure to the NMDA receptor antagonist, MK-801. We also investigated their role in serum/nutrient deprivation stress. The exogenous NSCs exerted neuroprotective effects against both types of apoptotic injuries considered as in vitro schizophrenic disease models. Exogenous NSCs also altered cellular survival signaling in injured neurons by indirect cell-cell contact in an injury-dependent manner. In MK-801 exposure, NSCs increased phosphorylated Akt (p-Akt) and ERK (p-ERK), both of which were reduced by this stress. While, in serum/nutrient deprivation, NSCs increased p-Akt, but decreased p-ERK which was increased by this damage. Our results demonstrate that exogenous NSCs have anti-apoptotic activities and can rescue cortical neurons by directing cellular survival signaling of neurons into the proper direction, without cell contact.
Positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose was performed in nine chronic schizophrenic patients both when medication-free and when medicated with neuroleptics. Total brain cortex, temporal cortex, and basal ganglia glucose use was significantly increased with medication; however, there was no change in anterior/posterior metabolic gradientsKeywords: Basal ganglia; Neuroleptics; Schizophrenia; Temporal cortex.
Positron emission tomography (PET) with 11C-2-deoxyglucose (11DG) was used to compare regional brain metabolism in four patients with chronic schizophrenia who had no history of psychotropic medication and in 12 normal controls. Patients had a second PET scan after an injection of thiothixene to evaluate the effects of acute neuroleptics on glucose metabolism. The patients showed higher glucose metabolic values than the normals and did not show the metabolic hypofrontality reported in chronic medicated patients with schizophrenia. Administration of the neuroleptic did not have a significant effect in the metabolic pattern of the patients. These results give support to the hypothesis that prolonged medication may contribute to the metabolic hypofrontal pattern seen in patients with schizophrenia.
We used magnetic resonance imaging to examine the morphologic characteristics of the amygdala/hippocampus, prefrontal cortex, and caudate nucleus in 29 healthy volunteers matched for age, gender, and head of household socioeconomic status and 44 patients with chronic schizophrenia. Total volumes of these structures were determined from 3-mm contiguous coronal sections. Schizophrenic patients, compared with healthy controls, had significantly smaller right and left amygdala/hippocampal complex volumes, smaller right and left prefrontal volumes, and larger left caudate volumes. A secondary analysis revealed reductions in the right and left amygdala and the left hippocampus. In addition, prefrontal white matter, but not gray matter, was reduced in the schizophrenic patients. Moreover, the right white matter volume in schizophrenic patients was significantly related to right amygdala/hippocampal volume (r = .39), data that provide preliminary support for a hypothesis of abnormal limbic-cortical connection in schizophrenia. We studied the implications of these data for the pathophysiology of schizophrenia.
This study examined the pathomorphology of the caudate nuclei in first-episode schizophrenic patients with minimal previous neuroleptic exposure.
Magnetic resonance imaging (MRI) of the brain was used to examine longitudinally the caudate pathomorphology in 29 first-episode schizophrenic patients and 10 healthy comparison subjects. MRI scans were obtained after the subjects entered the study and at 18-month follow-up. The patients were treated with standardized neuroleptic regimens during the 18-month period. Volumetric assessments of the cerebral cortex, lateral ventricles, and caudate nuclei were performed on T1-weighted coronal brain sections. In addition, the patients were systematically evaluated for psychopathology at baseline and during treatment.
Caudate volumes increased 5.7% in the patients during the 18-month treatment interval, whereas they decreased 1.6% in the comparison subjects over the same time period. Greater amounts of antipsychotic medication received by patients before the first scan and younger age at the time of the first scan were associated with larger increases in caudate volume.
Caudate enlargement occurs early in the course of treatment in young first-episode schizophrenic patients. This may be a result of an interaction between neuroleptic treatment and the plasticity of dopaminergic neuronal systems in young patients.
The effect of clozapine on striatal morphology was examined in adolescents with childhood-onset schizophrenia.
Eight adolescent patients with onset of psychosis before age 12 and eight matched comparison subjects had initial and 2-year follow-up brain magnetic resonance imaging scans. Basal ganglia and lateral ventricle volumes were measured. The patients were on a clozapine regimen during the 2-year interim.
Caudate volume was larger in the patients at the initial scanning, decreased in the patients between scans, and did not differ significantly between the patients and the comparison subjects at the second scanning.
Caudate enlargement in patients with childhood-onset schizophrenia who are taking typical neuroleptics appears to be secondary to medication exposure. Rescanning to examine basal ganglia morphology is indicated for these patients when they are taking an atypical neuroleptic.
Previous studies, mostly involving neuroleptic-treated patients, have suggested enlarged basal ganglia size in schizophrenia. The authors sought to examine basal ganglia volume in neuroleptic-naive psychotic patients.
Magnetic resonance imaging volumetric studies were conducted in newly diagnosed neuroleptic-naive schizophrenic and non-schizophrenic psychotic patients and in matched healthy comparison subjects.
Both patient groups had bilaterally reduced caudate, but not putamen, volumes, compared to the healthy subjects, after adjustment for intracranial volume.
Decreases in caudate volume in newly diagnosed psychotic patients may be related to the primary pathophysiology of these disorders; prior observations of increased caudate volume may reflect effects of neuroleptic treatment.
This study examined whether subcortical volumes of the basal ganglia and thalamus in schizophrenic patients are related to neuroleptic exposure and symptom severity.
Basal ganglia substructures and thalamic volumes were measured with magnetic resonance imaging in 96 patients with schizophrenia (50 men and 46 women) and 128 healthy comparison subjects (60 men and 68 women). Twenty-one of the patients were neuroleptic-naive; of the 75 previously treated patients, 48 had received typical neuroleptics only, and 27 had received typical and atypical neuroleptics. The relation of volume measures to treatment status, exposure to neuroleptics, and symptoms was examined.
The neuroleptic-naive patients did not differ from the healthy comparison subjects in subcortical volumes except for lower thalamic volume. In the neuroleptic-naive group, volumes did not correlate with severity of negative symptoms, but higher volumes in both the thalamus and the putamen were associated with more severe positive symptoms. The previously treated group showed higher volumes in the putamen and globus pallidus than the healthy comparison subjects and the neuroleptic-naive patients. In the treated group, a higher dose of a typical neuroleptic was associated with higher caudate, putamen, and thalamus volumes, whereas a higher dose of an atypical neuroleptic was associated only with higher thalamic volume. Higher subcortical volumes were mildly associated with greater severity of both negative and positive symptoms.
Increased subcortical volumes in treated schizophrenic patients seem to be medication-induced hypertrophy. This hypertrophy could reflect structural adaptation to receptor blockade and may moderate the effects of neuroleptic treatment.
Functional imaging gives us increasingly detailed information about the location of brain activity. To use this information, we need a clear conception of the meaning of location data. Here, we review methods for reporting location in functional imaging and discuss the problems that arise from the great variability in brain anatomy between individuals. These problems cause uncertainty in localization, which limits the effective resolution of functional imaging, especially for brain areas involved in higher cognitive function.
Structural neuroimaging studies have suggested an association between schizophrenia and abnormalities in brain morphology such as ventricular enlargement and differences in gray matter distribution. Less consistently reported are findings of regional abnormalities such as selective differences in thalamic volume. The authors applied an unbiased technique to test for differences in cerebral morphometry between patients with schizophrenia and matched comparison subjects.
T(1)-weighted images from 20 schizophrenic patients and matched comparison subjects were processed by using optimized automated voxel-based morphometry within multiple linear regression analyses.
Global differences in gray matter volume were seen between the schizophrenic and comparison subjects, with selective regional gray matter differences noted in the mediodorsal thalamus and across cortical regions, including the ventral and medial prefrontal cortices. Within the schizophrenic subjects, a relationship was observed between gray matter volume loss in the medial prefrontal cortex and a positive family history of schizophrenia. There was no significant difference between patients and comparison subjects in rates of proportional gray matter reduction with age.
These observations confirm an association between thalamocortical morphometric abnormalities and schizophrenia, consistent with theoretical models of primary pathoetiological dysfunction in filtering, integration, and information transfer processes in patients with schizophrenia.
• Neuropathologic and brain imaging studies have produced evidence of brain abnormalities in schizophrenic patients, often within the cerebrum's limbic lobe, and, less frequently, within basal ganglia. In the present study we used magnetic resonance imaging morphometric techniques to estimate volumes of specific cerebral structures in schizophrenic patients and age- and sex-matched normal controls. Estimates of the volume of mesial temporal lobe structures were reduced and estimates of the volume of the lenticular nucleus were increased in the schizophrenic patients. There was also evidence of reduced cranial volume in some schizophrenics. The magnitude of the lenticular abnormality, but not the temporal lobe abnormality, was associated with age at first psychiatric contact; earlier onset was associated with larger lenticular nuclei. The possible relevance of these results to neurodevelopmental hypotheses about the pathogenesis of schizophrenia is discussed.
Presents findings from magnetic resonance imaging (MRI) studies of patients with schizophrenia (SCZ), focusing on (1) findings that have helped distinguish patients who respond well to typical neuroleptics from those who have gone on to trials of clozapine (CZP), (2) the capacity of morphological measures to predict CZP treatment response, and (3) the possibility that selective hypertrophy of striatal structure may be caused by chronic treatment with typical neuroleptics, but not by CZP. Findings support a link between mesiotemporal pathology and persistent positive symptoms of SCZ. Predictive validity of abnormal brain morphology is discussed, and the potential of the study of treatment effects on the basal ganglia is considered. Studies of gross anatomical change may offer insight into the potentially unique actions of CZP relative to typical antipsychotic agents. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
We used voxel-based morphometry (VBM) to examine human brain asymmetry and the effects of sex and handedness on brain structure in 465 normal adults. We observed significant asymmetry of cerebral grey and white matter in the occipital, frontal, and temporal lobes (petalia), including Heschl's gyrus, planum temporale (PT) and the hippocampal formation. Males demonstrated increased leftward asymmetry within Heschl's gyrus and PT compared to females. There was no significant interaction between asymmetry and handedness and no main effect of handedness. There was a significant main effect of sex on brain morphology, even after accounting for the larger global volumes of grey and white matter in males. Females had increased grey matter volume adjacent to the depths of both central sulci and the left superior temporal sulcus, in right Heschl's gyrus and PT, in right inferior frontal and frontomarginal gyri and in the cingulate gyrus. Females had significantly increased grey matter concentration extensively and relatively symmetrically in the cortical mantle, parahippocampal gyri, and in the banks of the cingulate and calcarine sulci. Males had increased grey matter volume bilaterally in the mesial temporal lobes, entorhinal and perirhinal cortex, and in the anterior lobes of the cerebellum, but no regions of increased grey matter concentration.
At its simplest, voxel-based morphometry (VBM) involves a voxel-wise comparison of the local concentration of gray matter between two groups of subjects. The procedure is relatively straightforward and involves spatially normalizing high-resolution images from all the subjects in the study into the same stereotactic space. This is followed by segmenting the gray matter from the spatially normalized images and smoothing the gray-matter segments. Voxel-wise parametric statistical tests which compare the smoothed gray-matter images from the two groups are performed. Corrections for multiple comparisons are made using the theory of Gaussian random fields. This paper describes the steps involved in VBM, with particular emphasis on segmenting gray matter from MR images with nonuniformity artifact. We provide evaluations of the assumptions that underpin the method, including the accuracy of the segmentation and the assumptions made about the statistical distribution of the data.
Voxel-based-morphometry (VBM) is a whole-brain, unbiased technique for characterizing regional cerebral volume and tissue concentration differences in structural magnetic resonance images. We describe an optimized method of VBM to examine the effects of age on grey and white matter and CSF in 465 normal adults. Global grey matter volume decreased linearly with age, with a significantly steeper decline in males. Local areas of accelerated loss were observed bilaterally in the insula, superior parietal gyri, central sulci, and cingulate sulci. Areas exhibiting little or no age effect (relative preservation) were noted in the amygdala, hippocampi, and entorhinal cortex. Global white matter did not decline with age, but local areas of relative accelerated loss and preservation were seen. There was no interaction of age with sex for regionally specific effects. These results corroborate previous reports and indicate that VBM is a useful technique for studying structural brain correlates of ageing through life in humans.
Magnetic resonance imaging and positron emission tomography were used to study the size and metabolic rate of the caudate and the putamen in 18 patients with schizophrenia (n=16) or schizo-affective disorder (n=2) and 24 age- and sex-matched control subjects.
The patients were either never medicated (n=7) or drug free (n=11) for a median of 3 weeks. During uptake of fludeoxyglucose F 18, all patients performed a serial verbal learning test. Positron emission tomographic and magnetic resonance imaging scans were coregistered, and the caudate and the putamen were traced on the magnetic resonance image.
The striatum had a significantly lower relative metabolic rate in schizophrenics than in controls. Never-medicated patients had lower metabolic rates in the right putamen (ventral part of the dorsal striatum) than previously medicated patients. The caudate was significantly smaller in never-medicated patients than in controls and largest in previously medicated patients. Patients with higher relative metabolic rates in the putamen scored higher on the Abnormal Involuntary Movements Scale.
The findings are consistent with reports of striatal enlargement in previously medicated patients and size increases after neuroleptic treatment. Never-medicated patients, in contrast, had ventral striatal structures that were smaller and less active than those observed in controls and previously medicated patients.
Cerebral glucose metabolism was measured twice in a sample of 15 schizophrenics and eight controls, using positron emission tomography (PET) with 18-F-fluorodeoxyglucose. Studies were separated by three to 33 weeks. Patients were unmedicated during the first study, and the majority were receiving neuroleptics during the second study. There were no changes from study 1 to study 2 in average whole-brain metabolic rates, regional cortical activity, or the gradient of subcortical to cortical activity. The steeper subcortical to cortical gradient in schizophrenics, present in the first study, persisted in the second. Changes in this gradient were uncorrelated with changes in clinical status. Laterality (right-left) was stable across studies, and changes toward higher right relative to left hemispheric metabolism were correlated with clinical improvement. The results support the hypothesis of abnormal hemispheric activity in schizophrenia and implicate the subcortical-cortical gradient as another dimension that merits further exploration.
Image registration is a key step in a great variety of biomedical imaging applications. It provides the ability to geometrically align one dataset with another, and is a prerequisite for all imaging applications that compare datasets across subjects, imaging modalities, or across time. Registration algorithms also enable the pooling and comparison of experimental findings across laboratories, the construction of population-based brain atlases, and the creation of systems to detect group patterns in structural and functional imaging data. We review the major types of registration approaches used in brain imaging today. We focus on their conceptual basis, the underlying mathematics, and their strengths and weaknesses in different contexts. We describe the major goals of registration, including data fusion, quantification of change, automated image segmentation and labeling, shape measurement, and pathology detection. We indicate that registration algorithms have great potential when used in conjunction with a digital brain atlas, which acts as a reference system in which brain images can be compared for statistical analysis. The resulting armory of registration approaches is fundamental to medical image analysis, and in a brain mapping context provides a means to elucidate clinical, demographic, or functional trends in the anatomy or physiology of the brain.
The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287–294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein. Fos, which is thought to assist in the regulation of “target genes” containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined.
Volumetric measurements of subcortical and temporal structures were done on a sample of 54 schizophrenic patients, who were compared with 48 bipolar patients and 47 normal controls. We observed the male schizophrenic patients to have significant enlargement in the putamen and lesser enlargement in the caudate. We found the right temporal lobe to be larger than the left across all diagnostic groups, although bipolar females failed to have this asymmetry. We did not replicate the finding of decreased hippocampal, amygdala, or temporal lobe volume in our schizophrenic patients. Nor did we find significant differences between our bipolar patients and controls in the structures measured, with the exception of the right hippocampus. Our findings are consistent with a developmental defect in pruning of subcortical brain regions or with a compensatory synaptic increase secondary to decreased input from other brain regions such as the prefrontal cortex or anterior temporal lobe structures. Coupled with the lack of temporal lobe asymmetry in bipolar females, these findings suggest that different types of gender-specific neurodevelopmental abnormalities may occur in affective versus schizophrenic psychosis, which may reflect the effects of hormonal influences on brain development in predisposed individuals.
Twelve patients with schizophrenia received positron emission tomography scans with 18F-deoxyglucose before and after 4 to 6 weeks of treatment with clozapine or thiothixene. Both stereotaxic and magnetic resonance image template methods were used to position regions of interest for metabolic rate analysis. Clozapine increased and thiothixene decreased metabolic rates in the basal ganglia; these effects were most marked on the right side. Within the basal ganglia, a superior to inferior gradient in drug effect was found for thiothixene but not clozapine. This gradient resembled in some respects observations on regional differences in D2 receptors in human autoradiography. Baseline metabolic rates also predicted clinical medication response, with right inferior caudate metabolic rates differentiating clozapine and thiothixene responders. Larger sample studies are needed to replicate and extend these initial findings.
This study compares the effects of two neuroleptic drugs with different pharmacologic characteristics (thiothixene and haloperidol) on cerebral glucose utilization in chronic schizophrenic inpatients. Positron emission tomographic (PET) scans were obtained from all subjects in a neuroleptic-free condition and again after 4-6 weeks of neuroleptic treatment. Eight subjects were treated with thiothixene and 12 with haloperidol. Thiothixene and haloperidol had different metabolic effects. For example, all thiothixene-treated subjects showed increased whole brain glucose utilization; all but one haloperidol-treated subject showed decreased utilization. Different patterns of relative prefrontal and striatal metabolism were also observed. These results highlight the importance of controlling for the effects of neuroleptic treatment and indicate the difficulty of interpreting data from studies with complex or poorly defined drug regimens.
Neuropathologic and brain imaging studies have produced evidence of brain abnormalities in schizophrenic patients, often within the cerebrum's limbic lobe, and, less frequently, within basal ganglia. In the present study we used magnetic resonance imaging morphometric techniques to estimate volumes of specific cerebral structures in schizophrenic patients and age- and sex-matched normal controls. Estimates of the volume of mesial temporal lobe structures were reduced and estimates of the volume of the lenticular nucleus were increased in the schizophrenic patients. There was also evidence of reduced cranial volume in some schizophrenics. The magnitude of the lenticular abnormality, but not the temporal lobe abnormality, was associated with age at first psychiatric contact; earlier onset was associated with larger lenticular nuclei. The possible relevance of these results to neurodevelopmental hypotheses about the pathogenesis of schizophrenia is discussed.
Postmortem volumetry of cortex, white matter, and basal ganglia was performed in 23 brains of schizophrenic patients and 23 brains of controls closely matched for gender, age, and hemisphere. Stereological methods were applied to serial coronal sections of complete hemispheres. We found no significant volume changes of cortex and white matter in schizophrenics. Striatal volume of schizophrenics was increased bilaterally reaching a significant level on the left side. Volumes of the globus pallidus were increased in both hemispheres reaching a significant level on the right side. After psychopathological differentiation, basal ganglia volume increase was also found in the subgroup of paranoid-hallucinatory schizophrenics.
Glucose metabolic rate in the basal ganglia, thalamus, and somatosensory cortex was examined in eight patients with schizophrenia before and after receiving neuroleptic medication. Basal ganglia metabolic rates were increased with medication: more on the right than on the left and more in putamen than caudate. The cortical anteroposterior ratio, an index of relative hypofrontality, was not affected by neuroleptics. The brain areas that were found to be altered by neuroleptics were selected for comparison between off-medication schizophrenics and controls. Metabolic rates in the basal ganglia tended to be low in patients with schizophrenia in comparison to 24 age- and sex-matched controls.
The need for a simply applied quantitative assessment of handedness is discussed and some previous forms reviewed. An inventory of 20 items with a set of instructions and response- and computational-conventions is proposed and the results obtained from a young adult population numbering some 1100 individuals are reported. The separate items are examined from the point of view of sex, cultural and socio-economic factors which might appertain to them and also of their inter-relationship to each other and to the measure computed from them all. Criteria derived from these considerations are then applied to eliminate 10 of the original 20 items and the results recomputed to provide frequency-distribution and cumulative frequency functions and a revised item-analysis. The difference of incidence of handedness between the sexes is discussed.
Studies of brain morphology in schizophrenia may be informative about basic pathophysiologic processes, provide clinically useful indicators of treatment response, and lead to the identification of markers for selective treatment effects. This paper reviews findings from magnetic resonance imaging studies of patients with schizophrenia conducted at Hillside Hospital, with special attention to (1) findings that have helped distinguish patients who respond well to typical neuroleptics from those who have gone on to trials of clozapine, (2) the capacity of morphological measures to predict clozapine treatment response, and (3) the possibility that selective hypertrophy of striatal structure may be caused by chronic treatment with typical neuroleptics, but not by clozapine.
Clozapine and haloperidol produce different induction patterns of c-fos expression in the forebrain, with haloperidol increasing Fos-like immunoreactivity (FLI) in the striatum, nucleus accumbens, lateral septal nucleus and clozapine producing such effects in the nucleus accumbens, prefrontal cortex and lateral septal nucleus. Accordingly, it was deemed possible that this approach may be useful in characterizing compounds with known or suggested antipsychotic actions. We therefore examined the effects of 17 compounds considered to be either typical, or atypical, antipsychotics on FLI in the prefrontal cortex, medial and dorsolateral striatum, nucleus accumbens and the lateral septal nucleus. Consistent with the hypothesis that the prefrontal cortex may be a target for some antipsychotic actions, FLI was elevated in this structure by clozapine, ICI 204,636, fluperlapine, RMI-81,582, remoxipride, molindone, melperone and tiospirone. Likewise, the ability of all of the compounds, except for risperidone, to enhance FLI in the lateral septal nucleus suggests that this limbic region also may be an important locus of antipsychotic action. All of the compounds examined elevated FLI in the nucleus accumbens and medial striatum, indicating that potential antipsychotic activity is predicted most consistently on this basis. Neuroleptics with a clearly documented liability for producing extrapyramidal side effects (EPS) such as chlorpromazine, fluphenazine, haloperidol, loxapine, metoclopramide and molindone elevated FLI in the dorsolateral striatum. In contrast, compounds unlikely to produce EPS such as clozapine, thioridazine, risperidone, remoxipride, fluperlapine, sulpiride, melperone and RMI-81,582 either failed to increase or produced minor elevations in FLI in the dorsolateral striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Previous studies have shown elevation of neurotensin neuromedin N (NT/N) and c-fos mRNA in the dorsolateral region of the rat neostriatum (DLSt) by acute administration of only typical antipsychotic drugs. However, NT/N mRNA in the nucleus accumbens-shell is enhanced acutely by several clinically efficacious antipsychotic drugs, regardless of their motor side effect liability. In the present study, induction of NT/N mRNA in the DLSt was observed again after 28 days of continuous administration (via osmotic minipumps) of haloperidol, but not clozapine. However, this response was only about 50% of that caused by acute haloperidol and c-fos mRNA levels in the DLSt were not elevated after the chronic treatment. An acute challenge of haloperidol 24 hr after chronic haloperidol treatment did not affect the tolerant response of NT neurons but caused a small increase in c-fos mRNA in the DLSt. Similar to the DLSt, chronic haloperidol (but not clozapine) significantly enhanced NT/N gene expression in the ventrolateral striatum, a region thought to be involved in abnormal oral movements, perhaps related to tardive dyskinesia. Interestingly, dopamine D2 receptor binding using [125I]iodosulpride nearly doubled in all regions of the striatum after chronic haloperidol but not clozapine. In contrast to the lateral neostriatum, NT/N mRNA expression in the nucleus accumbens-shell was elevated similarly by chronic treatment with haloperidol and clozapine to a level observed after acute haloperidol treatment. These results demonstrate further that region-specificity of NT/N mRNA regulation discriminate between typical and atypical antipsychotic drugs.
Acute administration of the typical neuroleptic haloperidol (HAL, 2 mg/kg) induced the immediate-early gene proteins (IEGPs) c-Fos, Fos-related antigens (FRAs), FosB, JunB, JunD and Krox24 in the striatum and nucleus accumbens of the rat brain. In contrast, acute administration of the atypical antipsychotic drug clozapine (CLOZ, 30 mg/kg) induced only FRAs, JunB and Krox24 IEGPs in the striatum, and c-Fos, FRAs, and Krox24 IEGPs in the nucleus accumbens. c-Jun was not induced by acute administration of HAL or CLOZ in the rat brain. Differential induction of IEGs by HAL and CLOZ was also observed in the lateral septal nucleus and the islands of Calleja complex of the rat brain. These differences in IEG induction by HAL and CLOZ may be related to the different clinical profiles of the two drugs. Specifically, CLOZ induces FRAs in the islands of Calleja and lateral septum and this action may be involved in its therapeutic effects on the negative symptoms of schizophrenia, whereas HAL produces a coordinate induction of Fos and JunB in striatal neurons and this dimer combination may be involved in producing the extrapyramidal side-effects of typical neuroleptics.
Atypical antipsychotic drugs related to clozapine may be distinguishable from typical antipsychotic drugs by having a greater potency in vitro at serotonin2 (5-HT2) receptors relative to dopamine2 (D2) receptors. The in vivo potencies of 10 typical and 10 putative atypical antipsychotic drugs in occupying D2 and 5-HT2 receptors in rat brain are reported here. There is no significant difference in the average potency of the two groups of antipsychotic drugs in preventing the in vivo binding of N-[3H] methylspiperone to 5-HT2 receptors in the cortex. However, the average potency of the atypical antipsychotic drugs is about 8-fold less than typical antipsychotic drugs in preventing N-[3H] methylspiperone binding to D2 receptors in the striatum. Thus, all of the atypical antipsychotic drugs that are clozapine-like have a greater relative affinity in vivo for the 5-HT2 than the D2 receptor. As a group, the typical antipsychotic drugs tend to be equipotent at both receptors. The average relative potency of the group of typical antipsychotic drugs at 5-HT2 vs. D2 receptors is essentially equal when examined in vivo vs. in vitro. Atypical antipsychotic drugs are slightly but significantly more potent in vivo at D2 receptors in the olfactory tubercle than the striatum. For only the typical antipsychotic drugs, the in vivo and in vitro potencies in occupying D2 receptors are correlated with their average clinical dosage. Thus, the relative in vivo potency of clozapine-related drugs at 5-HT2 vs. D2 receptors may help identify these compounds as atypical antipsychotic drugs.
The functional pathways through which antipsychotic drugs act in the brain to decrease psychosis remain unknown, despite our knowledge that their site of initial action is through blockade of dopamine D2 receptors. The authors sought to define the brain regions that are functionally altered by neuroleptic drugs.
Regional cerebral glucose metabolism was studied in 12 subjects with schizophrenia while they were receiving a fixed dose of haloperidol, again 5 days after withdrawal of the drug, and a third time 30 days after withdrawal. Positron emission tomography with an [18F]fluorodeoxyglucose tracer was used in a within-subject design.
The analysis demonstrated a decrease in glucose metabolism in the caudate and putamen 30 days after withdrawal, indicating that haloperidol treatment enhanced glucose utilization in these areas. The thalamus, bilaterally but only in anterior areas, showed the same response to haloperidol. Only in the frontal cortex and in the anterior cingulate had metabolism increased 30 days after withdrawal, indicating that in those two cortical areas haloperidol depressed glucose metabolism. In the 5-day drug free scans, no regions differed significantly from those in the haloperidol condition, despite numerical changes.
It appears that 5 days of neuroleptic withdrawal are inadequate to escape the effects of neuroleptic drugs on regional cerebral glucose metabolism. The pattern and localization of changes in metabolic activity between the haloperidol condition and the 30-day drug-free condition suggest that haloperidol exerts its primary antidopaminergic action in the basal ganglia. It is proposed that the additional changes in the thalamus and cortex are secondary to this primary site of drug action, mediated through classically described striato-thalamo-cortical pathways.
Compared to typical antipsychotic drugs, clozapine produces a unique pattern of Fos-like immunoreactive neurons in the rat forebrain. It has been proposed, therefore, that this approach may be useful in identifying other agents with clozapine's therapeutic profile. In the present study, we examined the ability of olanzapine to increase the number of Fos-like immunoreactive neurons in the striatum, nucleus accumbens, lateral septal nucleus, and prefrontal cortex. Olanzapine (5, 10 mg/kg) produced dose-dependent increases in the number of Fos-positive neurons in the nucleus accumbens and lateral septal nucleus, important components of the limbic system that may mediate some of the therapeutic actions of neuroleptics. Olanzapine also produced dose-dependent increases in the number of Fos-positive neurons in the dorsolateral striatum, an effect that correlates with the ability of neuroleptics to produce extrapyramidal side-effects. The effects of olanzapine on regional c-fos expression are not therefore identical to clozapine, which is without effect in the dorsolateral striatum. However, olanzapine-induced increases in the dorsolateral striatum were considerably smaller than those generated in the nucleus accumbens suggesting that at low, potentially therapeutic doses olanzapine may not generate significant extrapyramidal side effects. Olanzapine also increased the number of Fos-positive neurons in medical prefrontal cortex, an action unique to clozapine and a few other atypical antipsychotics. These findings are consistent with the hypothesis that olanzapine is an atypical antipsychotic in the sense that it does not produce significant extrapyramidal side-effects at low therapeutic doses. However, extrapyramidal side-effects at higher doses can be predicted by these results. Finally, olanzapine's actions in the medial prefrontal cortex may be predictive of a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Additional clinical experience with olanzapine and other new antipsychotics is required to test the validity of these hypotheses.
This review examines the possible receptor basis of the atypical action of those atypical antipsychotic drugs that elicit low levels of Parkinsonism. Such an examination requires consistent and accurate dissociation constants for the antipsychotic drugs at the relevant dopamine and serotonin receptors. It has long been known, however, that the dissociation constant of a given antipsychotic drug at the dopamine D2 receptor varies between laboratories. Although such variation depends on several factors, it has recently been recognized that the radioligand used to measure the competition between the antipsychotic drug and the radioligand is an important variable. The present review summarizes information on this radioligand dependence. In general, a radioligand of low solubility in the membrane (i.e., low tissue:buffer partition) results in a low value for the antipsychotic dissociation constant when the drug competes with the radioligand. Hence, by first obtaining the antipsychotic dissociation constants using different radioligands of different solubility in the membrane, one can then extrapolate the data to low or "zero" ligand solubility. The extrapolated value represents the radioligand-independent dissociation constant of the antipsychotic. These values are here given for dopamine D2 and D4 receptors, as well as for serotonin 5-HT2A receptors. These values, moreover, agree with the dissociation constant directly obtained with the radioactive antipsychotic itself. For example, clozapine revealed a radioligand-independent value of 1.6 nM at the dopamine D4 receptor, agreeing with the value directly measured with [3H]-clozapine at D4. However, because clozapine competes with endogenous dopamine, the in vivo concentration of clozapine (to occupy dopamine D4 receptors) can be derived to be about 13 nM, agreeing with the value of 12 to 20 nM in the plasma water or spinal fluid observed in treated patients. The atypical neuroleptics remoxipride, clozapine, perlapine, seroquel, and melperone had low affinity for the dopamine D2 receptor (radioligand-independent dissociation constants of 30 to 90 nM). Such low affinity makes these latter five drugs readily displaceable by high levels of endogenous dopamine in the caudate or putamen. Most typical neuroleptics have radioligand-independent values of 0.3 to 5 nM at dopamine D2 receptors, making them more resistant to displacement by endogenous dopamine. Finally, a relation was found between the neuroleptic doses for rat catalepsy and the D2:D4 ratio of the radioligand-independent K values for these two receptors. Thus, the atypical neuroleptics appear to fall into two groups, those that have a low affinity for dopamine D2 receptors and those that are selective for dopamine D4 receptors.
Positron Emission Tomography (PET) imaging of regional cerebral blood flow (rCBF) provides an in vivo method for studying brain function. We used [15O]H20 PET to assess the effect of antipsychotic medications on rCBF in 17 subjects with schizophrenia. Each subject was scanned while receiving antipsychotic medication, and after having been withdrawn from antipsychotic medication for a 3-week period. The two scans were subtracted from one another, using a within subjects design, and the areas of difference were identified using the Montreal method. Subjects treated with antipsychotic medication had significantly higher rCBF in the left basal ganglia and left fusiform gyrus compared with the "off-medication" condition. Significantly higher relative rCBF in the anterior cingulate, left dorsolateral and inferior frontal cortex, and left and right cerebellum was observed when off antipsychotic medication. Upregulation of dopamine D2 receptors may lead to a regional increase of blood flow and metabolism in the basal ganglia, which may explain recently reported anatomical enlargement in these regions.
This paper presents a method for the coregistration and partitioning (i.e., tissue segmentation) of brain images that have been acquired in different modalities. The basic idea is that instead of matching two images directly, one performs intermediate within-modality registrations to two template images that are already in register. One can use a least-squares minimization to determine the affine transformations that map between the templates and the images. By incorporating suitable constraints, a rigid body transformation which directly maps between the images can be extracted from these more general affine transformations. A further refinement capitalizes on the implicit normalization of both images into a standard space. This facilitates segmentation or partitioning of both original images into homologous tissue classifications. Once partitioned, the partitions can be jointly matched, further increasing the accuracy of the coregistration. In short, these techniques reduce the between-modality problem to a series of simpler within-modality problems. These methods are relatively robust, address a number of problems in image transformations, and require no manual intervention.
Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens.
Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging.
Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine.
Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.
Multicenter trials with the novel antipsychotic risperidone have suggested a standard dose of 6 mg/day. However, a dose producing the highest response rate in fixed-dose studies is likely to exceed the minimal effective dose in most patients. The aim of this positron emission tomography (PET) study was to suggest a minimal effective dose of risperidone based on measurements of dopamine D2 and serotonin 5-HT2A receptor occupancy.
Eight first-episode or drug-free schizophrenic patients were treated with risperidone, 6 mg/day, for 4 weeks and then 3 mg/day for 2 weeks. PET was performed after 4 and 6 weeks, with [11C]raclopride to measure D2 receptor occupancy and [11C]N-methylspiperone to measure 5-HT2A receptor occupancy.
Seven patients completed the study and responded to treatment with risperidone. No patient had extrapyramidal side effects at the time of inclusion in the study. At the 6-mg/day dose, mean D2 receptor occupancy was 82% (range = 79%-85%), 5-HT2A receptor occupancy was 95% (range = 86%-109%), and six patients had developed extrapyramidal side effects. After dose reduction to 3 mg/day, D2 receptor occupancy was 72% (range = 53%-78%), and 5-HT2A receptor occupancy was 83% (range = 65%-112%). Three patients had extrapyramidal side effects at this time.
Treatment with risperidone, 6 mg/day, is likely to induce unnecessarily high D2 receptor occupancy, with a consequent risk of extrapyramidal side effects. High 5-HT2A receptor occupancy did not prevent extrapyramidal side effects completely. The authors previously suggested an optimal interval for D2 receptor occupancy of 70%-80%. To achieve this, resperidone, 4 mg/day, should be a suitable initial dose for antipsychotic effect with a minimal risk of extrapyramidal side effects in most patients.
For many years, it has been assumed that medications affect brain chemistry and physiology but not structure. Recent reports suggest that neuroleptic medication changes basal ganglia volume. To explore this possibility, the authors assessed for basal ganglia volume change in individuals who had their basal ganglia structures delineated and measured on magnetic resonance scans at the beginning and end of a 2-year period and who received neuroleptic medication during this time.
The basal ganglia volumes of 23 male patients with schizophrenia spectrum disorders were measured from manual traces delineating the caudate and lenticular nucleus on magnetic resonance images at admission and 2 years later. Patients' neuroleptic exposure was calculated over the 2 years by using a dose-year formula.
During the 2-year period, mean basal ganglia volume of patients receiving predominantly typical neuroleptics increased, while the opposite was observed for patients receiving mostly atypical neuroleptics. Correlation analysis for the entire group showed a positive relationship between the 2-year exposure to typical neuroleptic medication and change in basal ganglia volume and the reverse for exposure to atypical neuroleptics.
In this group, basal ganglia volume increased following exposure to typical neuroleptics and decreased following exposure to atypical neuroleptics.
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.
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.
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).
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.
Functional imaging studies indicate that delusions and hallucinations in schizophrenia are associated with overactivity of the left hippocampus and ventral striatum. Hippocampal neuronal firing modulates feedback to cortex via cortico-striato-thalamic loops.
To test the hypothesis that recovery from psychosis is associated with decrease in activity in cortico-striato-thalamic circuits, and, furthermore, that reduction in hippocampal activity predicts the degree of alleviation of delusions and hallucinations.
Positron emission tomography (PET) was used to measure the effects of the atypical antipsychotic, risperidone, on glucose metabolism in eight first-episode schizophrenia patients.
A single dose of risperidone produced decreases in metabolism in ventral striatum, thalamus and frontal cortex. The magnitude of decreases in left hippocampus predicted subsequent reduction in delusions and hallucinations. After six weeks' treatment with risperidone, the decreases in frontal metabolism were more extensive.
The mechanism of antipsychotic action of risperidone entails reduction of hippocampal activity together with reduced feedback via cortico-striato-thalamic loops.
Background:
Beginning with Kraepelin, schizophrenia has been viewed as a progressive disorder. Although numerous studies of the longitudinal course of schizophrenia have demonstrated the clinical deterioration that occurs predominantly in the early stages of the illness, the pathophysiology of this clinical phenomenon has not been established. This aspect of the illness may be of critical importance to understanding the pathogenesis of schizophrenia and determining preventive therapeutic strategies. Abnormalities in brain morphology have been consistently described in schizophrenia, but it is not known when in the natural history of the illness they arise and whether they are progressive. Previous studies of brain morphology have been inconclusive, in part because of the variability of methods for image acquisition and analysis, assessment of patients already at chronic stages of their illness with extensive prior treatment exposure, and inadequate periods of follow-up.
Methods:
To address these questions we examined 107 patients in their first episode of schizophrenia or schizoaffective disorder and 20 healthy volunteers using high resolution magnetic resonance imaging (MRI) and clinical assessments of psychopathology and treatment outcome for periods of up to 6 years. Fifty-one patients and 13 control subjects had MRIs after at least 12 months of follow-up.
Results:
Results confirm the findings of ventricular enlargement and anterior hippocampal volume reductions in first episode schizophrenia patients that have been previously reported. In addition, we found changes in selected structures over time in relation to treatment outcome, including increases in ventricular volume that were associated with poor outcome patients. Contrary to our hypothesis, there were no significant reductions in cortical and hippocampal volumes over time.
Conclusions:
The finding of progressive ventricular enlargement in patients with poor outcome schizophrenia is consistent with the hypothesis that persistent positive and negative symptoms result in progressive brain changes in the form of ventricular enlargement, possibly due to neurodegeneration rather than the confounding effects of treatment. Future studies of first episodes of schizophrenia should utilize higher resolution imaging techniques that compare clinically well characterized patients with and without poor outcome and recurrent symptoms to control subjects who are well matched to patients for age and gender. There is also a need to control for treatment effects of typical antipsychotic medication on brain structure.
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.
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.
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.
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.
Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function.
Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow.
Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol.
The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.
John Ashburner and Karl Friston (2000) introduced a standardized method of "voxel-based morphometry" (VBM) for comparisons of local concentrations of gray matter between two groups of subjects. Segmented images of gray matter from grossly normalized high-resolution images are smoothed and their group differences analyzed by the now-conventional voxelwise Worsley approach to Gaussian random fields of differences. This comment concerns an unfortunate interaction between the algorithm's spatial normalization and voxelwise comparison steps, whereby several obvious quantitative confounds are injected at the core of the inference engine the authors put forward. Specifically, the statistics of the resulting voxelwise comparisons are uninformative about group differences wherever the spatial normalization algorithm has failed to register on any robustly appearing image gradient. The method of Ashburner and Friston is defensible only far from all image gradients.
This paper reviews the evidence that antipsychotic drugs induce neuroplasticity. We outline how the synaptic changes induced by the antipsychotic drug haloperidol may help our understanding of the mechanism of action of antipsychotic drugs in general, and how they may help to elucidate the neurobiology of schizophrenia. Studies have provided compelling evidence that haloperidol induces anatomical and molecular changes in the striatum. Anatomical changes have been documented at the level of regional brain volume, synapse morphology, and synapse number. At the molecular level, haloperidol has been shown to cause phosphorylation of proteins and to induce gene expression. The molecular responses to conventional antipsychotic drugs are predominantly observed in the striatum and nucleus accumbens, whereas atypical antipsychotic drugs have a subtler and more widespread impact. We conclude that the ability of antipsychotic drugs to induce anatomical and molecular changes in the brain may be relevant for their antipsychotic properties. The delayed therapeutic action of antipsychotic drugs, together with their promotion of neuroplasticity suggests that modification of synaptic connections by antipsychotic drugs is important for their mode of action. The concept of schizophrenia as a disorder of synaptic organization will benefit from a better understanding of the synaptic changes induced by antipsychotic drugs.
We investigated anterior cingulate gyrus (ACG) volume in 40 patients with schizophrenia (20 males, 20 females) and 40 age-and sex-matched normal controls using three-dimensional magnetic resonance imaging (MRI). Volumes of the whole brain and both the gray and white matter of the ACG were measured on consecutive coronal 1-mm slices. There was no significant difference between the patients with schizophrenia and the normal controls in the whole brain volume. Right ACG gray matter volume was significantly reduced in the female patients with schizophrenia as compared with the female controls. Furthermore.in the female controls, ACG gray matter volume was significantly larger on the right than on the left, while this asymmetry was not significant in the female patients. ACG white matter findings were similar to those of the ACG gray matter in that the volume was significantly larger on the right in the female controls, and this normal structural asymmetry was reduced in the female patients. These results suggest that gender may play an important role in the structural asymmetry anomalies in schizophrenia.
Frontal-subcortical circuits form the principal network, which mediate motor activity and behavior in humans. Five parallel frontal-subcortical circuits link the specific areas of the frontal cortex to the striatum, basal ganglia and thalamus. These frontal-subcortical circuits originate from the supplementary motor area, frontal eye field, dorsolateral prefrontal region, lateral orbitofrontal region and anterior cingulate portion of the frontal cortex. The open afferent and efferent connections to the frontal-subcortical circuits mediate coordination between functionally similar areas of the brain. Specific chemoarchitecture and multiple neurotransmitter interactions modulate the functional activity of each circuit. Dorsolateral prefrontal circuit lesions cause executive dysfunction, orbitofrontal circuit lesions lead to personality changes characterized by disinhibition and anterior cingulate circuit lesions present with apathy. The neurobiological correlates of neuropsychiatric disorders including depression, obsessive-compulsive disorder, schizophrenia and substance abuse, imply involvement of frontal-subcortical circuits.