Reply: A few remarks on assessing magnocellular sensitivity in patients with schizophrenia

Reply: A few remarks on assessing magnocellular sensitivity in patients with schizophrenia
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  LETTER TO THE EDITOR Reply: A few remarks on assessing magnocellular sensitivity in patients with schizophreniaPamela D. Butler, 1,2,3 Antigona Martinez, 1  John J.Foxe, 1,3 Dongsoo Kim, 1 Vance Zemon, 4 Gail Silipo, 1  Jeannette Mahoney, 1,4 Marina Shpaner, 1,3 Maria Jalbrzikowski1and Daniel C. Javitt 1,2,3 1 Nathan Kline Institute for Psychiatric Research,Orangeburg,NY,  2 Department of Psychiatry, NewYork University School of Medicine, NewYork, NY,  3 City College of the City University of NewYork and  4 Ferkauf Graduate School of Psychology,Yeshiva University, Bronx, NY,USACorrespondence to: Pamela D. Butler, PhD, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd,Orangeburg NY10962,USAE-mail: butler@nki.rfmh.orgdoi:10.1093/brain/awm154 Received April 24, 2007. Revised June 8, 2007. Accepted June 8, 2007. Advance Access publication July12, 2007 Sir, Drs Skottun and Skoyles have written a critique of ourpaper ‘Subcortical visual dysfunction in schizophreniadrives secondary cortical impairments.’ We appreciatetheir interest in our paper and the opportunity toparticipate in scientific dialogue.Our paper examines early visual processing in schizo-phrenia using two sets of stimuli. In Experiment 1 we usedisolated checks of 4, 8, 16, 32 and 64% luminance contrastpresented for 60ms. The low contrast (4, 8%) stimuliwere used to bias processing towards the magnocellularpathway, while the higher contrast stimuli were consideredto activate both magnocellular and parvocellular pathways.In Experiment 2 we used high luminance contrast (80%)gabor patches (horizontal gratings with a gaussianenvelope) of 1.0 cycle/degree (low spatial frequency: LSF)and 5.0 cycles/degree (high spatial frequency: HSF)presented for 100ms. The LSF stimuli were used to biasprocessing towards the magnocellular pathway and theHSF stimuli were used to bias processing towards theparvocellular pathway.The correspondents assert that because our stimuli inExperiment 2 were above threshold, they cannot beconsidered selective for the magnocellular or parvocellularpathway. They also criticize our use of low contrast inExperiment 1 to bias processing towards the magnocellularpathway and state that ‘under most conditions, it is theparvocellular, not the magnocellular system, that respondsto the lowest contrast.’ Finally, they criticize our inter-pretation of our results. We gave the correspondentsexplicit feedback in response to a prior draft of theirletter, including numerous literature citations, some of which they incorporated into their published critique andthe rest they have chosen to ignore. We were and are awareof the literature they cite. Bridging the gap betweenperception or gross electrophysiology and the responsecharacteristics of single neurons, much of which is knownfrom studies on animals, necessarily involves speculation.Even given this latitude in educated opinions, however, wehave to disagree with the arguments put forth by Skottunand Skoyles and feel that they have reached theirconclusions in error.First, we would like to point out that, contrary to theassertions of the correspondents, we never claimed that ourstimuli completely isolated the magnocellular or theparvocellular system. No stimuli, including the onesadvocated by the correspondents, can be expected toentirely segregate systems. We were therefore careful inour paper to use the terms ‘magnocellular-biased’ and‘parvocellular-biased’ with regard to the stimuli, and havebeen careful to do so in our response. Also, as we noted inour original manuscript, it is critical to distinguish thesubcortical magnocellular and parvocellular pathways fromthe cortical dorsal and ventral streams.We would also like to point out that use of threshold-level stimuli, which are effective for psychophysicalexperiments, are impractical for event-related potential(ERP) studies. We (Butler  et al  ., 2005) and others(Slaghuis, 1998; Keri  et al  ., 2002) have shown reducedcontrast sensitivity, which by definition reflects contrastthreshold, in schizophrenia. Such experiments, however,depend upon behavioural rather than electrophysiologicalmeasures. In the present study, the measure is amplitude of scalp-recorded electrical activity, which provides morespecific information regarding neurophysiological responsepatterns in early visual regions. As shown by the 4%contrast data in Experiment 1, responses are extremely small to near threshold stimuli and signal-to-noise ratio islow. Thus, such stimuli are not optimal for ERP studies. Brain  (2007), 130 , e84  The Author (2007).Publishedby Oxford University Pressonbehalfofthe Guarantorsof Brain. Allrightsreserved.For Permissions, please email:   b  y g u e  s  t   on J   un e 1  0  ,2  0 1  3 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   Our stimuli in Experiment 1, which evaluated responsesacross a range of contrasts, allowed us to examine contrastgain control for the ERP response function. Contrary to theassertions of the correspondents, we feel that the non-linearnature of this function parallels the known magnocellularresponse function quite well. Neurons in other brainregions, such as MT, also receive magnocellular input andalso show similar response functions. The high contrast LSFand HSF stimuli used in Experiment 2 provide robustresponses which differentially activate dorsal versus ventralstream structures in normal volunteers, as predicted by their preferential activation of the magnocellular versusparvocellular pathways, respectively.With regard to their arguments concerning spatialfrequency, we feel that the correspondents mischaracterizethe available data on two levels. First, we note that inhumans, magnocellular cells have lower resolving ability than those found in monkeys, indicating that theirresponses are more biased toward lower spatial frequencies.This is because the dendritic fields of parasol (M) cells,but not midget (P) cells, are much larger in humans thanin monkeys (Dacey and Petersen, 1992). In humans,at 3 degrees of eccentricity, M cells have a 10-fold greaterdendritic field diameter than do P cells, which is expectedto yield quite different receptive field sizes and spatialtuning functions. In central retina, the dendritic fields of Mcells are about twice as large in humans as in macaquesresulting in a 4-fold difference in area. Dacey and Petersen(1992) state that ‘this result predicts that the human parasolcells should show a lower resolving ability and an increasedsensitivity to luminance contrast than their equivalents inthe macaque.’ Thus, human M cells should exhibit lowerspatial frequency tuning as well as higher contrastsensitivity than macaque M cells, and greater differencesbetween M- and P-cell function would be seen in humansthan in monkeys. In addition, other key differences havebeen observed in cortical recipients of magnocellularafferents in humans versus monkeys (e.g. Preuss andColeman, 2002). Thus, absolute spatial frequency valuesfrom monkey studies cannot be applied blindly to thehuman literature.Secondly, even within the monkey literature, the picturepainted by Skottun and Skoyles is not fully accurate.They cite ‘characteristic frequencies’ from Levitt  et al  .(2001) of 3.55 and 4.57 cycles/degree, respectively, asindicating that the spatial frequency response patterns of magnocellular and parvocellular neurons are similar. This isa misleading quotation, as characteristic frequencies arevery different from peak frequencies. Characteristicfrequencies are the corner frequencies—the point atwhich the response of a given mechanism (e.g. receptivefield centre) begins to fall off with regard to spatialfrequency. Thus, this value is relatively uninformative withregard to response characteristics at the low spatialfrequency end of the response range. The values cited by Levitt  et al  . (2001), however, do support our contentionthat responses to 5 cycles/degree stimuli (our HSF stimuli)would stimulate parvocellular neurons more than magno-cellular neurons, which show a steep drop-off in monkeysover the 3.55 cycles/degree value quoted. In addition,in Levitt  et al  . (2001), the difference between the 3.55 and4.57 cycles/degree characteristic frequencies is statistically significant ( P  5 0.02). The differences are likely even greaterin humans based on the anatomical work of Dacey andPetersen (1992).As opposed to characteristic frequency, there are otherparameters in the monkey literature that do provideinformation about relative low spatial frequency responsein magnocellular versus parvocellular neurons. For instance,in single-cell studies of monkey lateral geniculate nucleus(LGN), Derrington and Lennie (1984) report that magno-cellular cells have peak responses at lower spatial frequen-cies than do parvocellular cells for a criterion well abovethreshold (Figures 8 and 13). In addition, Tootell  et al  .(1988 b ) using high contrast (70%) stimuli, found that HSFgratings produced much higher uptake of 2DG in 4C b  of primary visual cortex (which receives input from theparvocellular LGN layers), whereas LSF stimuli producedthe opposite results with greater uptake in 4C a  (whichreceives input from magnocellular LGN layers). Tootell et al  . (1988 b ) state that ‘Presumably, cells in themagnocellular LGN layers and/or in the magnocellular-dominated layer 4C a  have lower average spatial frequency tuning (larger receptive fields) than their counterparts inthe parvocellular LGN and/or in striate layer 4C b .’We also feel that the correspondents fail to cite theappropriate literature with regard to our use of isolated-check stimuli and contrast manipulation to bias activity toward the magnocellular pathway. In discussing contrastmanipulation, the correspondents choose to ignore thesame monkey single-cell studies that they cite with regardto spatial resolution (e.g. Kaplan and Shapley, 1982;Spear  et al  ., 1994; Levitt  et al  ., 2001). These studies show unequivocally that magnocellular neurons have greatercontrast gain and respond at lower contrast than doparvocellular neurons. Cortical recipients of magnocellularinput respond to low contrast whereas those receivingparvocellular input do not respond until contrast attains atleast   8% (Tootell  et al  ., 1988 a ). Also, the correspondentsdo not cite the lesion literature accurately. Although they quote the literature as stating that ‘the largest deficits incontrast sensitivity in fact occur following parvocellularlesions,’ they neglect to mention that the finding is only for static stimuli (Merigan and Maunsell, 1993). Theisolated-check stimuli that we used in the contrastexperiment were presented with abrupt onset and offsetfor a brief duration of 60ms, which corresponds to atransient condition with considerable high temporalfrequency content. Also, the stimulus pattern had low spatial frequency composition (  1.3 cycles/degree), asnoted explicitly by the correspondents. Merigan  et al  .(1991 a ) explicitly state that ‘Magnocellular lesions greatly  e84  Brain  (2007), 130  Letter to the Editor   b  y g u e  s  t   on J   un e 1  0  ,2  0 1  3 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   reduced detection contrast sensitivity at high temporal andlow spatial frequencies,’ while the correspondents them-selves point out that ‘reductions in contrast sensitivity following lesions in the magnocellular layers are mainly confined to cases where stimuli of both low spatial andhigh temporal frequency are employed (Schiller  et al  .,1990 a ,  b ; Merigan and Maunsell, 1990; Merigan  et al  .,1991 a ,  b ; Merigan and Maunsell, 1993).’ This is thesituation that pertains to our stimuli.The correspondents also cite Legge (1978) to say that thecontrast threshold of a 3 cycles/degree grating ‘associatedwith the parvocellular system’ is 0.13%. However, the Legge(1978) statement pertains to stimuli of 3000ms duration,which are much longer than the duration used in thepresent paradigm (  100ms). As noted by the correspon-dents themselves, the length of stimulation is a critical issuein comparing data across studies, as integration time in theparvocellular (sustained) system is far longer than in themagnocellular (transient) system. In fact, Legge (1978)demonstrates that LSF conditions of 100ms duration or lessemphasize the transient system, which the correspondentsthemselves claim to be equivalent to the magnocellularpathway.Thus, psychophysical work in both monkeys andhumans, which includes lesion studies in monkeys, are inagreement that a low spatial frequency stimulus (e.g. 1cycle/degree) presented at moderately high temporalfrequency selectively activates the transient mechanism(Legge, 1978) and magnocellular pathway (Merigan  et al  .,1991 a ; Merigan and Maunsell, 1993) as we assert in ourstudy.We would also like to note that the isolated-check stimuli have been used in several previous VEP studies,most recently by Zemon and Gordon (2006). In thesestudies, the stimuli appear to have served their intendedpurpose, i.e. biased responses in favour of magnocellular orparvocellular activity depending on contrast manipulations.For instance, as contrast increases in the low to moderaterange, the VEP response functions exhibit amplitudecompression and phase advance for magnocellular-biasedstimuli, which is consistent with responses obtainedfrom M-type cells in the retina and lateral geniculatenucleus of monkeys (Derrington and Lennie, 1984; Kaplanand Shapley, 1986).We appreciate that the correspondents have taken thetime and effort to perform a Fourier analysis of ourisolated-check stimuli. Contrary to their claims, however,their analysis actually supports our contention that thesestimuli are magnocellularly biased. We claimed in ourarticle that isolated-check stimuli were magnocellularly biased at low contrast. As they show, the main Fouriercomponents are at a low spatial frequency (1.3 cycles/degree) and the secondary higher spatial frequency components have greatly reduced energy, and thuswould not be expected to contribute much to the responseat low contrast. It is quite possible that these stimuliare biased toward the magnocellular system even athigher contrasts.The correspondents miscite our article in criticizing ourconclusions. Their critique is based upon the assertion that‘Butler  et al  . (2007) associate the ventral cortical streamwith parvocellular activity  . . . ’ This is untrue. In fact, in ourpaper (p. 418) we state quite clearly that there is ‘someconvergence of magnocellular and parvocellular input evenin V1 (Sawatari and Callaway, 1996; Vidyasagar  et al  ., 2002)and significant interaction between dorsal and ventralstreams occurring thereafter.’ Thus, in particular, theventral stream receives direct input from the parvocellularpathway, and crossover input from the magnocellularpathway via secondary visual regions (e.g. V3A) (Chen et al  ., 2006). Only the correspondents incorrectly equate thesubcortical parvocellular pathway and the cortical ventralstream pathways.In their critique they ignore the major finding of ourstudy, i.e. that the decreased C1, P1 and N1 amplitudesin the transient VEPs are found only to LSF, not HSF,stimuli, as shown in Table 3 of the paper. In our study,many patterns of results were possible. We could haveobserved normal activity, in which case we would haveconcluded that early visual processing in schizophrenia wasintact. We could have observed reduced C1, P1, or N1activity regardless of stimulus type, in which case we wouldhave concluded that the cortical region or mechanismgenerating that component was specifically affected.What we observed, however, is that responses startingwith C1 and continuing with P1 and N1 were deficient toLSF, but not HSF, stimuli. We concluded that the mostparsimonious explanation for this finding is that thesubcortical pathway providing LSF input to cortex (i.e. magnocellular pathway), rather than cortex itself, wasimpaired. This conclusion was buttressed by the fact thatpatients also showed reduced ERP generation to low (4, 8%) contrast stimuli. Such stimuli also bias activity toward the magnocellular pathway.Finally, some assertions by the correspondents simply confuse us. For example, they state that ERP deficits,because they measure cortical activity, ‘could be the resultof deficiencies anywhere along the visual pathways (i.e. inthe visual optics, photoreceptors, retinal ganglion cells,LGN cells) . . . ’ This is certainly true, although the last twonodes (retinal ganglion cells, LGN cells) are componentsof the magnocellular pathway and so would fall within ourhypothesis. It is hard to see how difference in opticswould yield the results that we obtained. With regard tooptics, we note that all subjects were corrected to vision of 20/30 or better. Under our photopic conditions, thesame photoreceptors (cones) contribute to the M- andP-pathways and thus are unlikely to cause a differentialdeficit.These issues were all pointed out to the correspondentsin our response to the previous draft of their letter. Wenote that they did make some corrections to their srcinal Letter to the Editor  Brain  (2007), 130  e84   b  y g u e  s  t   on J   un e 1  0  ,2  0 1  3 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om   letter in response to our initial comments (e.g. Skottun andSkoyles had srcinally stated that there was no low spatialfrequency attenuation in parvocellular response functions).However, they have failed to either acknowledge or refutemost of our comments, but continue to make theirassertions. To us, it seems that they would be betterserved by conducting original studies using stimuli thatthey feel are optimal.We are gratified by the correspondents’ statement thatvisual pathway function is an important area of study inschizophrenia and that magnocellular dysfunction wouldhave ‘significant implications’ for understanding schizo-phrenia. We also believe that scientific exchange isextremely important. We wish, however, that Drs Skottunand Skoyles had examined a broader literature prior toformulating their critique, and that they had cited theextant literature, as well as our article, more accurately. Wehope that the literature reviewed and the arguments putforth here will be useful to others in designing experiments.As always, our hypotheses, like all scientific hypotheses, aretestable. Further work is needed to replicate our findings aswell as to provide a greater understanding of visualdysfunction and its implications in schizophrenia andother disorders. References Butler PD, Martinez A, Foxe JJ, Kim D, Zemon V, Silipo G, et al.Subcortical visual dysfunction in schizophrenia drives secondary corticalimpairments. Brain 2007; 130: 417–30.Butler PD, Zemon V, Schechter I, Saperstein AM, Hoptman MJ, Lim KO,et al. Early-stage visual processing and cortical amplification deficits inschizophrenia. 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Vision Res 2006; 46:4163–80. e84  Brain  (2007), 130  Letter to the Editor   b  y g u e  s  t   on J   un e 1  0  ,2  0 1  3 h  t   t   p :  /   /   b r  a i  n . oxf   or  d  j   o ur n a l   s  . or  g /  D o wnl   o a  d  e  d f  r  om 
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