Biomedical subjects

M S Keshavan

Publications and source records attributed to M S Keshavan.

At least 19 recordsLinked to original sources

PubMed2006

Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia.

Infectious agents have been proposed as one of the risk factors for schizophrenia. However, the data on the association of infectious agents with in vivo brain changes are scant. We evaluated the association of serological evidence of exposure to herpes simplex virus 1 (HSV1) with in vivo brain structural variations among first-episode antipsychotic-naive schizophrenia/schizoaffective disorder patients and control subjects. We assayed HSV1 immunoglobulin G (IgG) antibody in serum samples from 30 patients and 44 healthy subjects and obtained structural magnetic resonance imaging scans from the same individuals. There were proportionately more patients with elevated HSV1 antibody ratios than healthy comparison subjects (chi2=3.98, 1 df, P=0.046) and patients had significantly higher HSV1 IgG antibody ratios compared with healthy subjects. Using optimized voxel-based morphometry, we examined diagnosis by HSV1 serological status interaction followed by within- and between-group comparison across the serological status. We observed a diagnosis by HSV1 serological status interaction and a significant main effect of HSV1 serological status in the prefrontal gray matter. Patients exposed to HSV1 had decreased gray matter in Brodmann area 9 (dorsolateral prefrontal cortex) and 32 (anterior cingulate cortex) compared with patients without serological evidence of exposure to HSV1. HSV1-associated differences in brain structure were not detected among healthy subjects. These findings suggest that HSV1 exposure in schizophrenia is associated with specific regional gray matter differences that may not be attributable to medications, illness chronicity or comorbid substance use. This study provides suggestive evidence for a link between HSV1 exposure and some of the cerebral morphological changes often reported in schizophrenia.

Adolescent↗

PubMed2006

Are neurologic examination abnormalities heritable? A preliminary study.

BACKGROUND: Neurologic examination abnormalities (NEA) are more prevalent among patients with schizophrenia as well as their unaffected relatives when compared with healthy controls, suggesting that NEA may be endophenotypes for schizophrenia. We estimated the heritability of NEA in moderately sized pedigrees. We also evaluated correlations between NEA and cognitive performance in order to examine their construct validity. METHODS: Members of eight extended families, each consisting of two first degree relatives with schizophrenia/schizoaffective disorders, as well as available first- to fifth-degree relatives were examined (n=96 participants). A modification of the Neurological Evaluation Scale (NES) was employed, augmented with localizing signs. Where feasible, we used untransformed data such as error counts and completion time, rather than ordinal measures. Heritability was estimated using the variance component method, implemented in SOLAR. RESULTS: Statistically significant heritability (h2) estimates were obtained for several measures (p<0.05, h2+/-standard error: rapid alternating movements, right-sided completion time, 0.99+/-0.19; alternating fist-palm test, completion time, 0.77+/-0.19 s, errors, 0.70+/-0.32; fist-ring test, right-sided completion time, 0.53+/-0.23 s, left-sided completion time, 0.70+/-0.21 s; go-no go task, correct responses, 0.93+/-0.33; audio-visual integration, correct responses, 0.79+/-0.54). For most items, heritability analysis was hampered by insufficient data variability (infrequent errors). Correlational analyses show some degree of divergence among types of NEA, repetitive motor tasks being associated with most domains of cognitive functioning other than executive functioning, and cognitive-perceptual tasks being associated with memory and executive functioning. CONCLUSIONS: Significant familial influences on certain aspects of neurologic performance were detected. These heritable measures were also correlated with heritable neurocognitive measures.

Adolescent↗

PubMed2006

Cognitive correlates of a functional COMT polymorphism in children with 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11DS) is a common microdeletion syndrome associated with a markedly elevated risk of schizophrenia in adulthood. Cognitive impairments such as a low IQ and deficits in attention and executive function are common in childhood. The catechol O-methyltransferase (COMT) gene maps within the deleted region and is involved in the degradation of dopamine, a neurotransmitter thought to be important in cognition and the development of schizophrenia. Thus, we examined the correlation between neurocognitive deficits and a common polymorphism Val(158)Met in the COMT gene in a cohort of children with 22q11DS. Our results show that children with 22q11DS who have the Met allele have higher IQ and achievement scores and perform better on measures of prefrontal cognition, such as the Continuous Performance Task, as compared with those with the Val allele. These results confirm that the hemizygous COMT Val(158)Met genotype impacts upon cognition in children with 22q11DS.

Adolescent↗

PubMed2006

MRI volumetric and 31P MRS metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia.

OBJECTIVE: To examine the volumetric and metabolic correlates of caudate nucleus in antipsychotic-naïve schizophrenia patients in comparison with healthy controls. METHOD: Twelve antipsychotic-naïve schizophrenia patients and 13 healthy controls underwent (31)P magnetic resonance spectroscopy of basal ganglia. Magnetic resonance imaging volume of caudate nuclei was measured using scion image software. RESULTS: Patients had significantly smaller caudate volume than healthy controls. Phosphocreatine (PCr)/total phosphorous and PCr/total adenosine tri-phosphate ratios of both caudate nuclei were significantly lower in patients than controls. Significant negative correlation was found between the left caudate volume and left PCr/total phosphorus ratio in the patients. Age at onset of psychosis had i) significant negative correlation with right and left caudate volumes and ii) significant positive correlation with left PCr/total phosphorus ratio. CONCLUSION: The metabolic and volumetric abnormalities of caudate nucleus in antipsychotic-naïve schizophrenia patients support neurodevelopmental etiopathogenesis.

Adenosine Triphosphate↗

PubMed2005

Genetic polymorphisms of the RGS4 and dorsolateral prefrontal cortex morphometry among first episode schizophrenia patients.

Polymorphisms of the gene encoding the regulator of G-protein signaling subtype 4 (RGS4) may confer risk for schizophrenia.(1) DNA microarray studies of postmortem brain samples have shown RGS4 underexpression in the dorsolateral prefrontal cortex (DLPFC, area 9), motor and visual cortices in schizophrenia patients relative to control subjects.(2) Underexpression of RGS4 in DLPFC is pathophysiologically significant because DLPFC pathology in schizophrenia has been supported by neurocognitive,(3,4) structural(5) and functional(6,7) imaging, postmortem,(8) cellular(9,10) and molecular(11) pathological studies. For these reasons, we examined the association of DLPFC gray matter volume with RGS4 polymorphisms in a series of antipsychotic-naive first-episode schizophrenia patients and control subjects. We hypothesized that volumetric alterations of the DLPFC would be associated with RGS4 polymorphisms and that these differences would be more pronounced in patients than in controls. We observed robust volumetric differences across the genotypes in the pooled sample of patients and control subjects; when separately analyzed, we observed differences within the patient group (n = 30) but not in control subject (n = 27) group. The findings suggest that RGS4 polymorphisms may contribute to structural alterations in the DLPFC.

Adult↗

PubMed2004

Basal ganglia high-energy phosphate metabolism in neuroleptic-naive patients with schizophrenia: a 31-phosphorus magnetic resonance spectroscopic study.

OBJECTIVE: This study used 31-phosphorus magnetic resonance spectroscopy ((31)P MRS) to investigate basal ganglia abnormalities in neuroleptic-naive patients with schizophrenia. METHOD: Nineteen schizophrenia patients and 31 age- and sex-matched healthy comparison subjects underwent (31)P MRS. RESULTS: The phosphocreatine/total phosphorus and phosphocreatine/total ATP ratios in both basal ganglia were significantly lower in patients. CONCLUSIONS: Schizophrenia patients showed features of increased metabolism in the basal ganglia consistent with impaired activity of the frontostriatal pathways.

Adenosine Triphosphate↗

PubMed2004

Corpus callosum signal intensity in patients with bipolar and unipolar disorder.

BACKGROUND: Anatomical abnormalities in the corpus callosum have been reported in magnetic resonance imaging (MRI) studies in patients with bipolar but not unipolar disorder. MRI signal intensity can be used as a putative index of corpus callosum myelination. OBJECTIVES: To measure MRI signal intensity in patients with bipolar and unipolar disorder to investigate abnormalities of corpus callosum myelination. METHODS: The study involved 29 DSM-IV bipolar patients (mean (SD) age, 35 (11) years; 16 male, 13 female), 23 DSM-IV unipolar patients (41 (10) years; 4 male, 19 female), and 36 healthy controls (37 (10) years; 23 male, 13 female). A 1.5T GE Signa magnet was employed, with a fast spin echo sequence. Corpus callosum signal intensity was obtained blindly using the semiautomated software NIH Image 1.62. RESULTS: Bipolar patients had lower corpus callosum signal intensity for all callosal subregions (genu, anterior and posterior body, isthmus, splenium) than healthy controls (ANCOVA, age and sex as covariates, p<0.05). No significant differences were found between unipolar and healthy subjects (ANCOVA, age and sex as covariates, p>0.05). CONCLUSIONS: The findings suggest abnormalities in corpus callosum white matter in bipolar but not unipolar patients, possibly because of altered myelination. Such abnormalities could lead to impaired interhemispheric communication in bipolar disorder. Longitudinal MRI studies involving first episode and early onset bipolar patients will be necessary for a better understanding of the potential role of abnormalities of corpus callosum myelination in the pathophysiology of bipolar disorder.

Adult↗

PubMed2003

Neurological soft signs in never-treated schizophrenia.

OBJECTIVE: Studies of Neurological Soft Signs (NSS) in schizophrenia are confounded by handedness, inconsistent methodology, and prior treatment with neuroleptics. The study objective is to examine NSS in never-treated schizophrenia. METHOD: We examined the NSS in treatment-naïve schizophrenia patients (n = 21) and age, sex, education, and handedness matched normal controls (n = 21) using the modified Neurological Evaluation Scale with good inter-rater reliability. RESULTS: Schizophrenia patients had significantly more NSS than normals. No significant correlation was found between illness duration and NSS. CONCLUSION: Higher neurological signs in never-treated patients and their lack of association with illness duration suggest neurodevelopmental etiopathogenesis of schizophrenia.

Adult↗

PubMed2003

Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study.

In vivo (31)P magnetic resonance spectroscopy ((31)P MRS) studies have shown abnormal membrane phospholipid metabolism in the prefrontal cortex (PF) in the early course of schizophrenia. It is unclear, however, whether these alterations also represent premorbid risk indicators in schizophrenia. In this paper, we report in vivo (31)P MRS data on children and adolescents at high risk (HR) for schizophrenia. In vivo (31)P MRS studies of the PF were conducted on 16 nonpsychotic HR offspring of parents with schizophrenia or schizoaffective disorder, and 37 age-matched healthy comparison (HC) subjects. While 11 of the HR subjects had evidence of Axis I psychopathology (HR-P), five HR subjects had none (HR-NP). We quantified the freely mobile phosphomonoester (PME) and phosphodiester (PDE) levels reflecting membrane phospholipid precursors and breakdown products, respectively, and the relatively broad signal underlying PDE and PME peaks, comprised of less mobile molecules with PDE and PME moieties (eg, synaptic vesicles and phosphorylated proteins). Compared to HC subjects, HR subjects had reductions in freely mobile PME; the differences were accounted for mainly by the HR-P subjects. Additionally, HR-P subjects showed increases in the broad signal underlying the PME and PDE peaks in the PF. To conclude, these data demonstrate new evidence for decreased synthesis of membrane phospholipids and possibly altered content or the molecular environment of synaptic vesicles and/or phosphoproteins in the PF of young offspring at risk for schizophrenia. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.

Adolescent↗

PubMed2003

Measuring the corpus callosum in schizophrenia: a technique with neuroanatomical and cytoarchtectural basis.

BACKGROUND: Corpus Callosum (CC) abnormalities have been described in schizophrenia. Review of CC measurement methods in schizophrenia reveals inconsistency and lack of neuroanatomical basis. AIMS: The aims of the study are to describe a new CC measurement method with valid a neuroanatomical and cytoarchitectural basis and to demonstrate inter-rater reliability for the same. SETTINGS AND DESIGN: The study was performed in the National Institute of Mental Health & Neurosciences, Bangalore, India. Ours is a cross-sectional study in which both the first author and senior neuroradiologist were blind to clinical details. MATERIAL AND METHODS: We report a reliable, semi-automated CC measuring technique with a neuroanatomical and cytoarchitectural basis tested in a group of 16 never-treated schizophrenia patients using 1-mm thick, objectively defined midsagittal MRI section. Measurement on coded slices using scion image software ensured elimination of rater bias. STATISTICAL ANALYSIS USED: The statistical analysis used for assessing inter-rater reliability is intraclass correlation coefficient analysis. RESULTS: The intraclass correlation coefficients for the CC measurements were as follows: CC Area = 0.93; Anterior CC area = 0.84; Area of body of the CC = 0.83; Area of CC isthmus = 0.65; Area of CC splenium = 0.88; maximum antero-posterior distance of CC = 0.96. CONCLUSION: Measurements showed good inter-rater reliability. The methodology demonstrated in our study is simple, relevant, reliable and can be used for future schizophrenia research.

Brain↗

PubMed2002

Abnormalities of the corpus callosum in first episode, treatment naive schizophrenia.

BACKGROUND: Structural alterations in the association cortices as well as in the corpus callosum (CC) have been described in schizophrenia, and have been considered to reflect developmental abnormalities. Areas of primary and association cortices have been topographically mapped in the CC. OBJECTIVE: To investigate whether, in schizophrenia, there are alterations in CC subdivisions that connect association, but not primary, cortices, and also to see if the normative, developmentally mediated increase in CC size with age is absent in this disorder. METHODS: The midsagittal magnetic resonance imaging scans of 31 first episode, neuroleptic naive, schizophrenic patients, 12 non-schizophrenic, psychotic patients, and 31 healthy controls were compared. The total area of CC as well as that of anterior, middle and posterior genu, body, isthmus, and anterior, middle, and posterior splenii were measured. RESULTS: Patients with schizophrenia as a group had a smaller CC, anterior genu, anterior body, isthmus, and anterior splenium than normal controls. Furthermore, the age related increase in CC size seen in normal subjects was absent in the patients. CONCLUSIONS: The observed reductions in size in selected regions of CC suggest a reduction in axonal connections between the heteromodal association cortices, which typically involve small diameter fibres. Furthermore, the absence of an age related increase in CC size in patients with schizophrenia suggests a neurodevelopmental abnormality that may extend into adolescence and early adulthood.

Adult↗

PubMed2001

MRI study of thalamic volumes in bipolar and unipolar patients and healthy individuals.

The thalamus is a key structure in brain anatomic circuits potentially involved in the pathophysiology of mood disorders. Available findings from studies that examined this brain region in mood disorder patients have been conflicting. To examine the hypothesis of anatomical abnormalities in the thalamus in patients with mood disorders, we conducted a magnetic resonance imaging (MRI) study in 25 bipolar patients (mean age+/-S.D.=34.4+/-9.8 years), 17 unipolar patients (mean age+/-S.D.=42.8+/-9.2 years), and 39 healthy control subjects (mean age+/-S.D.=36.6+/-9.7 years). Thalamic volumes Gray Matter were measured blindly with a semi-automated technique. Multivariate analysis of variance, with age and gender as covariates, revealed no significant differences in left or right thalamic volumes among bipolar patients, unipolar patients and healthy individuals. There were no significant effects of gender, age at illness onset, episode type, number of episodes, length of illness, or family history of mood disorders on thalamic measurements. Although functional abnormalities in the thalamus are likely to be implicated in the pathophysiology of mood disorders, no abnormalities in thalamic size appear present in bipolar or unipolar individuals.

Adult↗

PubMed2001

Decreased pituitary volume in patients with bipolar disorder.

BACKGROUND: Neuroendocrinologic investigations in bipolar disorder have suggested abnormalities in pituitary function. However, few imaging studies have evaluated possible anatomical differences in this brain structure in mood disorder patients. Our aim was to examine potential abnormalities in pituitary volume in patients with bipolar and in a comparison group of patients with unipolar disorder. METHODS: We measured the volumes of the pituitary gland in 23 patients with bipolar disorder (mean +/- s.d. = 34.3 +/- 9.9 years) and 13 patients with unipolar disorder (41.2 +/- 9.6 years), and 34 healthy control subjects (36.6 +/- 9.6 years) using 1.5 mm thick T1-weighted coronal 1.5 T MRI images. All measurements were done blindly by a trained rater. RESULTS: Patients with bipolar disorder had significantly smaller pituitary volumes than healthy control subjects (mean volume +/- s.d. = 0.55 +/- 0.15 ml and 0.68 +/- 0.20 ml, respectively; ANCOVA, F = 8.66, p = 0.005), and than patients with unipolar disorder (0.70 +/- 0.12 ml, F = 5.98, p = 0.02). No differences were found between patients with unipolar disorder and healthy control subjects (F = 0.01, p = 0.91). CONCLUSIONS: To our knowledge, this is the first study that reports smaller pituitary volumes in bipolar disorder. Our findings suggest that detectable abnormalities in pituitary size are present in patients with bipolar disorder, which may reflect a dysfunctional HPA axis.

Adult↗

PubMed2001

Right amygdala volume in adolescent and young adult offspring from families at high risk for developing alcoholism.

BACKGROUND: Neurobiological factors have been implicated in the increased susceptibility for developing alcohol dependence that offspring from alcoholic families exhibit. The P300 component of the event-related potential shows developmental changes during childhood and adolescence that appear to be related to risk status. The underlying structural changes that accompany these neurophysiological changes are not well understood. METHODS: Magnetic resonance imaging was used to measure cerebral, amygdala, and hippocampal volumes in 17 high-risk adolescent and young adult offspring from multiplex alcoholism families and 17 age-, gender-, and IQ-matched control subjects without a family history for alcoholism or other substance dependence. Twenty-two of the subjects are part of a longitudinal prospective study and have been followed an average of 7.3 years, making it possible to relate P300 developmental trajectories to structural volumes. RESULTS: High-risk adolescents and young adults showed reduced right amygdala volume in comparison with control subjects. Right amygdala volume was significantly correlated with visual P300 amplitude. CONCLUSIONS: Offspring from families having a high density of alcoholism differ in both neurophysiological and neuroanatomical characteristics that could not be explained by personal drinking history or particular childhood and adolescent psychopathology. Because the amygdala tends to increase in volume during childhood and adolescence, smaller volumes in high-risk children may indicate a developmental delay that parallels delays seen in visual P300 amplitude.

Adolescent↗

PubMed2001

Anatomical MRI study of basal ganglia in bipolar disorder patients.

This study examined possible anatomical abnormalities in basal ganglia structures in bipolar disorder patients. Caudate and putamen gray matter volumes, and globus pallidus total volume were measured with magnetic resonance imaging (MRI) in 22 DSM-IV bipolar patients (age+/-S.D.=36+/-10 years; eight drug-free and 14 lithium monotherapy patients) and 22 matched healthy control subjects (age+/-S.D.=38+/-10 years). No significant differences were found between bipolar patients and healthy control subjects for any of the basal ganglia measures (t-tests, P>0.05). Age was inversely correlated with left putamen volumes in patients (R=-0.44, P=0.04), but not in healthy control subjects (R=-0.33, P=0.14). Older patients (>36 years old) had a significantly larger left globus pallidus than younger ones (< or =36 years old) (ANOVA, P=0.01). In a multiple regression analysis, after entering age as independent variable, the length of illness predicted smaller left putamen volumes, explaining 10.4% of the variance (F=4.07, d.f.=2, P=0.03). No significant effects of episode type, number of prior episodes, or gender were found in any basal ganglia measurements (ANOVA, P>0.05). In conclusion, our findings indicate that the basal ganglia may be anatomically preserved in bipolar patients. This is in contrast to available findings for unipolar disorder. However, our findings also suggest that age and length of illness may have significant effects on basal ganglia structures in bipolar patients, which may be more pronounced among bipolar I patients, and of relevance for the pathophysiology of the disorder.

Adult↗

PubMed2001

Brain lithium concentrations in bipolar disorder patients: preliminary (7)Li magnetic resonance studies at 3 T.

BACKGROUND: This study was conducted to investigate the feasibility of human brain (7)Li MRS investigations at a high magnetic field (3 T), and to further explore the relationship between brain and serum lithium measures in lithium-treated bipolar patients. METHODS: Eight bipolar disorder type I patients (5 males, 3 females; mean age +/- SD = 33 +/- 9 years) were studied. A 3-T scanner, using a dual-tuned ((1)H and (7)Li) echoplanar imaging (EPI) compatible radiofrequency (RF) birdcage coil was used. (7)Li magnetic resonance spectroscopy (MRS) signal was acquired at the frequency of 49.64 MHz using an imaging selective in vivo spectroscopy (ISIS) sequence (TR = 15 sec, 128 averages), and quantitation was obtained in reference to an external standard. RESULTS: The mean +/- SD oral lithium dose was 1265 +/- 442 mg/day, and the mean +/- SD 12-hour serum level was 0.69 +/- 0.19 mEq/L. The measured brain lithium concentrations varied from 0.23 to 0.55 mEq/L (mean +/- SD = 0.35 +/- 0.11 mEq/L). The brain-serum ratios varied from 0.30 to 0.80 (mean +/- SD = 0.52 +/- 0.16). Subjects on single daily doses of lithium at bedtime (n = 5) had higher brain-serum lithium ratios compared with those on twice-a-day schedules (n = 3) (0.61 +/- 0.12 and 0.37 +/- 0.07, respectively; Mann--Whitney U test, Z = -2.24, p =.03). CONCLUSIONS: This study demonstrated for the first time the feasibility of (7)Li MRS human studies at 3 T. Future studies should examine a possible role for this methodology in investigations of lithium refractoriness and prediction of treatment outcome in bipolar patients.

Adult↗

PubMed2001

Maturation of widely distributed brain function subserves cognitive development.

Cognitive and brain maturational changes continue throughout late childhood and adolescence. During this time, increasing cognitive control over behavior enhances the voluntary suppression of reflexive/impulsive response tendencies. Recently, with the advent of functional MRI, it has become possible to characterize changes in brain activity during cognitive development. In order to investigate the cognitive and brain maturation subserving the ability to voluntarily suppress context-inappropriate behavior, we tested 8-30 year olds in an oculomotor response-suppression task. Behavioral results indicated that adult-like ability to inhibit prepotent responses matured gradually through childhood and adolescence. Functional MRI results indicated that brain activation in frontal, parietal, striatal, and thalamic regions increased progressively from childhood to adulthood. Prefrontal cortex was more active in adolescents than in children or adults; adults demonstrated greater activation in the lateral cerebellum than younger subjects. These results suggest that efficient top-down modulation of reflexive acts may not be fully developed until adulthood and provide evidence that maturation of function across widely distributed brain regions lays the groundwork for enhanced voluntary control of behavior during cognitive development.

Adolescent↗

PubMed2001

Oculomotor delayed response abnormalities in young offspring and siblings at risk for schizophrenia.

Individuals with schizophrenia are know to demonstrate cognitive and behavioral difficulties, particularly alterations in executive functions, including working memory. It is unclear whether these deficits reflect trait-related vulnerability to schizophrenia indicators and can be assessed by studying nonpsychotic relatives of patients with schizophrenia. In this study, we used an oculomotor delayed response (ODR) paradigm to examine spatial working memory in 37 "high-risk" child and adolescent offspring and siblings (age range=6-25 years) of patients with schizophrenia or schizoaffective disorder. Compared with 37 age- and sex-matched healthy controls (age range=6-23 years), high-risk subjects showed nonsignificantly greater errors in the ODR task at longer delay intervals. Statistical analyses suggested that performance improved with age in healthy control subjects, whereas it worsened with age in high-risk subjects. In both groups, the ODR errors were generally associated with poorer sustained attention (Continuous Performance Test: visuospatial d prime), somewhat poorer executive function (Wisconsin Card Sorting Test), and elevated Heinrichs-Buchanan neurological soft signs scores. These findings indicate the presence of spatial working memory abnormalities in individuals at risk for schizophrenia. Furthermore, these abnormalities may be progressive in nature. The ODR task is a valuable indicator of prefrontal cortical function and spatial working memory and may be a potentially valuable marker for familial risk of schizophrenia.

Journal Article↗