Abstract
Minor motor and sensory deficits or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. Although previous studies have reported that NSS are associated with altered structure and function within fronto-parietal areas, it remains unclear whether the neuroanatomical basis of NSS may be confounded by underlying pathological processes, and by antipsychotic treatment. Morphological brain correlates of NSS in healthy subjects have seldom been investigated. This study evaluated the relationship between NSS levels and abnormalities of subcortical and cortical structures in healthy individuals. High-resolution MRI data at 3 Tesla were obtained from 68 healthy individuals. Automated segmentation of caudate nucleus, putamen, globus pallidus, thalamus, and brainstem was performed using both FSL-FIRST and Freesurfer. The surface-based analysis via Freesurfer enabled calculation of cortical thickness, area and folding (local gyrification index). NSS were examined on the Heidelberg Scale and related to both subcortical and cortical measurements. Using two fully automated brain segmentations methods, we found no significant association between NSS levels and morphological changes in subcortical structures. Higher NSS scores were associated with morphological changes of cortical thickness, area and folding in multiple areas comprising superior frontal, middle temporal, insular and postcentral regions. Our findings demonstrate the benefit of surface-based approaches when investigating brain correlates of NSS. The data lend further support to the hypothesis that NSS in healthy individuals involve multiple cortical rather than subcortical brain regions.
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References
Bachmann S, Bottmer C, Schroder J (2005) Neurological soft signs in first-episode schizophrenia: a follow-up study. Am J Psychiatry 162:2337–2343. doi:10.1176/appi.ajp.162.12.2337
Bersani G, Clemente R, Gherardelli S, Pancheri P (2004) Deficit of executive functions in schizophrenia: relationship to neurological soft signs and psychopathology. Psychopathology 37:118–123. doi:10.1159/000078610
Bhojraj TS et al (2011) Progressive alterations of the auditory association areas in young non-psychotic offspring of schizophrenia patients. J Psychiatr Res 45:205–212. doi:10.1016/j.jpsychires.2010.05.018
Binder J (1997) Functional magnetic resonance imaging. Language mapping. Neurosurg Clin N Am 8:383–392
Bombin I, Arango C, Buchanan RW (2005) Significance and meaning of neurological signs in schizophrenia: two decades later. Schizophr Bull 31:962–977. doi:10.1093/schbul/sbi028
Bottmer C et al (2005) Reduced cerebellar volume and neurological soft signs in first-episode schizophrenia. Psychiatry Res 140:239–250. doi:10.1016/j.pscychresns.2005.02.011
Buchanan RW, Heinrichs DW (1989) The neurological evaluation scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 27:335–350 0165-1781(89)90148-0 [pii]
Buckner RL, Head D, Parker J, Fotenos AF, Marcus D, Morris JC, Snyder AZ (2004) A unified approach for morphometric and functional data analysis in young, old, and demented adults using automated atlas-based head size normalization: reliability and validation against manual measurement of total intracranial volume. Neuroimage. doi:10.1016/j.neuroimage.2004.06.018
Cai L et al (2013) Neurological soft signs and their relationship with measures of executive function in Chinese adolescents. J Dev Behav Pediatr 34:197–203. doi:10.1097/DBP.0b013e3182825c41
Chan RC, Gottesman II (2008) Neurological soft signs as candidate endophenotypes for schizophrenia: a shooting star or a Northern star? Neurosci Biobehav Rev 32:957–971. doi:10.1016/j.neubiorev.2008.01.005
Chan RC, Xu T, Heinrichs RW, Yu Y, Wang Y (2010) Neurological soft signs in schizophrenia: a meta-analysis. Schizophr Bull 36:1089–1104. doi:10.1093/schbul/sbp011
Corbetta M, Miezin FM, Shulman GL, Petersen SE (1993) A PET study of visuospatial attention. J Neurosci 13:1202–1226
Corbo V, Clement MH, Armony JL, Pruessner JC, Brunet A (2005) Size versus shape differences: contrasting voxel-based and volumetric analyses of the anterior cingulate cortex in individuals with acute posttraumatic stress disorder. Biol Psychiatry 58:119–124. doi:10.1016/j.biopsych.2005.02.032
Cox SM, Ludwig AM (1979) Neurological soft signs and psychopathology. I. Findings in schizophrenia. J Nerv Ment Dis 167:161–165
Critchley M (1953) The parietal lobes. Hafner, New York
Cuesta MJ, Peralta V, Zarzuela A, Calvo R, García M, Serrano F (2002) Neurological soft-signs in psychosis: threshold criteria for discriminating normal controls and for predicting cognitive impairment. Schizophr Res 58(2–3):263–271
Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based analysis. I. Segmentation and surface reconstruction. NeuroImage 9:179–194. doi:10.1006/nimg.1998.0395
Dazzan P et al (2004) The structural brain correlates of neurological soft signs in AESOP first-episode psychoses study. Brain 127:143–153. doi:10.1093/brain/awh015awh015
Dazzan P et al (2006) The structural brain correlates of neurological soft signs in healthy individuals. Cereb Cortex 16:1225–1231. doi:10.1093/cercor/bhj063
Dean K et al (2006) Grey matter correlates of minor physical anomalies in the AeSOP first-episode psychosis study. Br J Psychiatry 189:221–228. doi:10.1192/bjp.bp.105.016337
DeLong (2000) The basal ganglia. In: Kandel ER, Schwartz JH, Jessell TM (eds) Principles of neural science, 4th edn. McGraw-Hill, New York, pp 647–659
Desikan RS et al (2006) An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 31:968–980. doi:10.1016/j.neuroimage.2006.01.021
Fischl B, Dale AM (2000) Measuring the thickness of the human cerebral cortex from magnetic resonance images. Proc Natl Acad Sci USA 97:11050–11055. doi:10.1073/pnas.200033797
Fischl B, Sereno MI, Dale AM (1999) Cortical surface-based analysis. II: inflation, flattening, and a surface-based coordinate system. NeuroImage 9:195–207. doi:10.1006/nimg.1998.0396
Fischl B et al (2002) Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron 33:341–355
Fischl B et al (2004) Automatically parcellating the human cerebral cortex. Cereb Cortex 14:11–22
Fornito A et al (2008) Surface-based morphometry of the anterior cingulate cortex in first episode schizophrenia. Hum Brain Mapp 29:478–489. doi:10.1002/hbm.20412
Fusar-Poli P et al (2012) Predicting psychosis: meta-analysis of transition outcomes in individuals at high clinical risk. Arch Gen Psychiatry 69:220–229. doi:10.1001/archgenpsychiatry.2011.1472
Fusar-Poli P (2012) The psychosis high-risk state: a comprehensive state-of-the-art review. Arch Gen Psychiatry. doi:10.1001/jamapsychiatry.2013.269
Gay O et al (2012) Cortex morphology in first-episode psychosis patients with neurological soft signs. Schizophr Bull. doi:10.1093/schbul/sbs083
Gehring WJ, Knight RT (2000) Prefrontal-cingulate interactions in action monitoring. Nat Neurosci 3:516–520. doi:10.1038/74899
Genovese CR, Lazar NA, Nichols T (2002) Thresholding of statistical maps in functional neuroimaging using the false discovery rate. NeuroImage 15:870–878. doi:10.1006/nimg.2001.1037
Goch CJ, Stieltjes B, Henze R, Hering J, Poustka L, Meinzer HP, Maier-Hein KH (2014) Quantification of changes in language-related brain areas in autism spectrum disorders using large-scale network analysis. Int J Comput Assist Radiol Surg. doi:10.1007/s11548-014-0977-0
Heinrichs DW, Buchanan RW (1988) Significance and meaning of neurological signs in schizophrenia. Am J Psychiatry 145:11–18
Hertzig ME, Birch HG (1968) Neurologic organization in psychiatrically disturbed adolescents. A comparative consideration of sex differences. Arch Gen Psychiatry 19:528–537
Heuser M, Thomann PA, Essig M, Bachmann S, Schroder J (2011) Neurological signs and morphological cerebral changes in schizophrenia: an analysis of NSS subscales in patients with first episode psychosis. Psychiatry Res 192:69–76. doi:10.1016/j.pscychresns.2010.11.009
Hirjak D, Wolf RC, Stieltjes B, Seidl U, Schroder J, Thomann PA (2012) Neurological soft signs and subcortical brain morphology in recent onset schizophrenia. J Psychiatr Res 46:533–539. doi:10.1016/j.jpsychires.2012.01.015
Hirjak D et al (2013) Neurological soft signs and brainstem morphology in first-episode schizophrenia. Neuropsychobiology 68:91–99. doi:10.1159/000350999
Hirjak D, Wolf RC, Stieltjes B, Hauser T, Seidl U, Schroder J, Thomann PA (2014a) Cortical signature of neurological soft signs in recent onset schizophrenia. Brain Topogr 27:296–306. doi:10.1007/s10548-013-0292-z
Hirjak D, Wolf RC, Wilder-Smith EP, Kubera KM, Thomann PA (2014b) Motor Abnormalities and Basal Ganglia in Schizophrenia: Evidence from Structural Magnetic Resonance Imaging. Brain Topogr [Epub ahead of print]
Honea R, Crow TJ, Passingham D, Mackay CE (2005) Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies. Am J Psychiatry 162:2233–2245. doi:10.1176/appi.ajp.162.12.2233
Janssen J et al (2009) Brain morphology and neurological soft signs in adolescents with first-episode psychosis. Br J Psychiatry 195:227–233. doi:10.1192/bjp.bp.108.052738
Kennard MA (1960) Value of equivocal signs in neurologic diagnosis. Neurology 10:753–764
Keshavan MS, Sanders RD, Sweeney JA, Diwadkar VA, Goldstein G, Pettegrew JW, Schooler NR (2003) Diagnostic specificity and neuroanatomical validity of neurological abnormalities in first-episode psychoses. Am J Psychiatry 160:1298–1304
Khan AR, Wang L, Beg MF (2008) FreeSurfer-initiated fully-automated subcortical brain segmentation in MRI using large deformation diffeomorphic metric mapping. Neuroimage 41:735–746. doi:10.1016/j.neuroimage.2008.03.024
Klein D et al (2014) Adolescent brain maturation and cortical folding: evidence for reductions in gyrification. PLoS One 9:e84914. doi:10.1371/journal.pone.0084914
Kong L, Bachmann S, Thomann PA, Essig M, Schroder J (2012) Neurological soft signs and gray matter changes: a longitudinal analysis in first-episode schizophrenia. Schizophr Res 134:27–32. doi:10.1016/j.schres.2011.09.015
Kuperberg GR et al (2003) Regionally localized thinning of the cerebral cortex in schizophrenia. Arch Gen Psychiatry 60:878–888. doi:10.1001/archpsyc.60.9.878
Leask SJ, Done DJ, Crow TJ (2002) Adult psychosis, common childhood infections and neurological soft signs in a national birth cohort. Br J Psychiatry 181:387–392
Li W, Qin W, Liu H, Fan L, Wang J, Jiang T, Yu C (2013) Subregions of the human superior frontal gyrus and their connections. Neuroimage 78:46–58. doi:10.1016/j.neuroimage.2013.04.011
Lishman WA (1978) Organic Psychiatry. Blackwell, Oxford
Liu Y, Li YJ, Luo EP, Lu HB, Yin H (2012) Cortical thinning in patients with recent onset post-traumatic stress disorder after a single prolonged trauma exposure. PLoS One 7:e39025. doi:10.1371/journal.pone.0039025
McGorry PD, McFarlane C, Patton GC, Bell R, Hibbert ME, Jackson HJ, Bowes G (1995) The prevalence of prodromal features of schizophrenia in adolescence: a preliminary survey. Acta Psychiatr Scand 92:241–249
Miller TJ et al (2003) Prodromal assessment with the structured interview for prodromal syndromes and the scale of prodromal symptoms: predictive validity, interrater reliability, and training to reliability. Schizophr Bull 29:703–715
Mittal VA, Walker EF (2007) Movement abnormalities predict conversion to Axis I psychosis among prodromal adolescents. J Abnorm Psychol 116:796–803. doi:10.1037/0021-843X.116.4.796
Mittal VA et al (2007) Movement abnormalities and the progression of prodromal symptomatology in adolescents at risk for psychotic disorders. J Abnorm Psychol 116:260–267. doi:10.1037/0021-843X.116.2.260
Mittal VA, Daley M, Shiode MF, Bearden CE, O’Neill J, Cannon TD (2010) Striatal volumes and dyskinetic movements in youth at high-risk for psychosis. Schizophr Res 123:68–70. doi:10.1016/j.schres.2010.08.002
Mittal VA et al (2013) Neurological soft signs predict abnormal cerebellar-thalamic tract development and negative symptoms in adolescents at high risk for psychosis: a longitudinal perspective. Schizophr Bull. doi:10.1093/schbul/sbt199
Mouchet-Mages S et al (2011) Correlations of cerebello-thalamo-prefrontal structure and neurological soft signs in patients with first-episode psychosis. Acta Psychiatr Scand 123:451–458. doi:10.1111/j.1600-0447.2010.01667.x
Nesvag R et al (2014) Reduced brain cortical folding in schizophrenia revealed in two independent samples. Schizophr Res 152:333–338. doi:10.1016/j.schres.2013.11.032
Oldfield RC (1971) The assessment and analysis of handedness: the Edinburgh inventory. Neuropsychologia 9:97–113
Palaniyappan L, Liddle PF (2012) Dissociable morphometric differences of the inferior parietal lobule in schizophrenia. Eur Arch Psychiatry Clin Neurosci. doi:10.1007/s00406-012-0314-y
Palaniyappan L, Liddle PF (2014) Diagnostic discontinuity in psychosis: a combined study of cortical gyrification and functional connectivity. Schizophr Bull 40:675–684. doi:10.1093/schbul/sbt050
Pardoe HR, Abbott DF, Jackson GD (2012) Sample size estimates for well-powered cross-sectional cortical thickness studies. Hum Brain Mapp. doi:10.1002/hbm.22120
Patenaude B, Smith S, Kennedy D, Jenkinson M (2011a) A bayesian model of shape and appearance for subcortical brain segmentation. NeuroImage. doi:10.1016/j.neuroimage.2011.02.046
Patenaude B, Smith SM, Kennedy DN, Jenkinson M (2011b) A bayesian model of shape and appearance for subcortical brain segmentation. Neuroimage 56:907–922. doi:10.1016/j.neuroimage.2011.02.046
Ridler K et al (2006) Fronto-cerebellar systems are associated with infant motor and adult executive functions in healthy adults but not in schizophrenia. Proc Natl Acad Sci USA 103:15651–15656. doi:10.1073/pnas.0602639103
Rochford JM, Detre T, Tucker GJ, Harrow M (1970) Neuropsychological impairments in functional psychiatric diseases. Arch Gen Psychiatry 22:114–119
Sauvage C, Jissendi P, Seignan S, Manto M, Habas C (2013) Brain areas involved in the control of speed during a motor sequence of the foot: real movement versus mental imagery. J Neuroradiol 40:267–280. doi:10.1016/j.neurad.2012.10.001
Schaer M, Cuadra MB, Tamarit L, Lazeyras F, Eliez S, Thiran JP (2008) A surface-based approach to quantify local cortical gyrification. IEEE Trans Med Imaging 27:161–170. doi:10.1109/TMI.2007.903576
Schaer M, Cuadra MB, Schmansky N, Fischl B, Thiran JP, Eliez S (2012) How to measure cortical folding from MR images: a step-by-step tutorial to compute local gyrification index. J Vis Exp JoVE. doi:10.3791/3417
Schilling C et al (2013) Cortical thickness of superior frontal cortex predicts impulsiveness and perceptual reasoning in adolescence. Mol Psychiatry 18:624–630. doi:10.1038/mp.2012.56
Schroder J, Niethammer R, Geider FJ, Reitz C, Binkert M, Jauss M, Sauer H (1991) Neurological soft signs in schizophrenia. Schizophr Res 6:25–30 (0920-9964(91)90017-L)
Schultz CC et al (2010) Reduced cortical thickness in first episode schizophrenia. Schizophr Res 116:204–209. doi:10.1016/j.schres.2009.11.001
Schultz CC et al (2011) Reduced cortical thickness is associated with the glutamatergic regulatory gene risk variant DAOA Arg30Lys in schizophrenia. Neuropsychopharmacology 36:1747–1753. doi:10.1038/npp.2011.56
Schulz KP, Bedard AC, Czarnecki R, Fan J (2011) Preparatory activity and connectivity in dorsal anterior cingulate cortex for cognitive control. Neuroimage 57:242–250. doi:10.1016/j.neuroimage.2011.04.023
Segonne F, Dale AM, Busa E, Glessner M, Salat D, Hahn HK, Fischl B (2004) A hybrid approach to the skull stripping problem in MRI. NeuroImage 22:1060–1075. doi:10.1016/j.neuroimage.2004.03.032
Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizophrenia. Schizophr Res 49:1–52
Sled JG, Zijdenbos AP, Evans AC (1998) A nonparametric method for automatic correction of intensity nonuniformity in MRI data. IEEE Trans Med Imaging 17:87–97. doi:10.1109/42.668698
Thomann PA, Roebel M, Dos Santos V, Bachmann S, Essig M, Schroder J (2009a) Cerebellar substructures and neurological soft signs in first-episode schizophrenia. Psychiatry Res 173:83–87. doi:10.1016/j.pscychresns.2008.07.006
Thomann PA, Wustenberg T, Santos VD, Bachmann S, Essig M, Schroder J (2009b) Neurological soft signs and brain morphology in first-episode schizophrenia. Psychol Med 39:371–379. doi:10.1017/S0033291708003656
Thomann PA, Hirjak D, Kubera KM, Stieltjes B, Wolf RC (2014) Neural network activity and neurological soft signs in healthy adults. Behav Brain Res 278C:514–519. doi:10.1016/j.bbr.2014.10.044
Torrey EF (2007) Schizophrenia and the inferior parietal lobule. Schizophr Res 97:215–225. doi:10.1016/j.schres.2007.08.023
Townsend JD et al (2012) Deficits in inferior frontal cortex activation in euthymic bipolar disorder patients during a response inhibition task. Bipolar Disord 14:442–450. doi:10.1111/j.1399-5618.2012.01020.x
Venkatasubramanian G, Jayakumar PN, Gangadhar BN, Keshavan MS (2008) Neuroanatomical correlates of neurological soft signs in antipsychotic-naive schizophrenia. Psychiatry Res 164:215–222. doi:10.1016/j.pscychresns.2007.12.021
Vogt BA, Vogt L, Laureys S (2006) Cytology and functionally correlated circuits of human posterior cingulate areas. Neuroimage 29:452–466. doi:10.1016/j.neuroimage.2005.07.048
Walther S, Strik W (2012) Motor symptoms and schizophrenia. Neuropsychobiology 66:77–92. doi:10.1159/000339456
Wittchen HU, Wunderlich U, Gruschwitz S, Zaudig M (1997) SKID-I: Strukturiertes klinisches Interview für DSM-IV. Hogrefe, Göttingen
Xiao Y et al (2013) Altered cortical thickness related to clinical severity but not the untreated disease duration in schizophrenia. Schizophr Bull. doi:10.1093/schbul/sbt177
Zhao Q et al (2013) Neurological soft signs are not “soft” in brain structure and functional networks: evidence from ALE meta-analysis. Schizophr Bull. doi:10.1093/schbul/sbt063
Zhou SY et al (2005) Volumetric analysis of sulci/gyri-defined in vivo frontal lobe regions in schizophrenia: precentral gyrus, cingulate gyrus, and prefrontal region. Psychiatry Res 139:127–139. doi:10.1016/j.pscychresns.2005.05.005
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Hirjak, D., Wolf, R.C., Kubera, K.M. et al. Multiparametric mapping of neurological soft signs in healthy adults. Brain Struct Funct 221, 1209–1221 (2016). https://doi.org/10.1007/s00429-014-0964-9
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DOI: https://doi.org/10.1007/s00429-014-0964-9