The human thalamus is crucially involved in executive control operations

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The human thalamus is crucially involved in executive control operations

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The human thalamus is crucially involved in executive control operations

  1. 1. The Human Thalamus is Crucially Involved in Executive Control Operations Frank Marzinzik, Michael Wahl, Gerd-Helge Schneider, Andreas Kupsch, Gabriel Curio, and Fabian KlostermannAbstract& The processing of executive control is thought to involve prepared movement had to be performed or withheld. In fronto-cortical as well as thalamic brain areas. However, the questions central scalp as well as in thalamic recordings, event-relatedof how thalamic structures contribute to the control of be- potentials upon go versus no-go instructions were expressedhavior and how cortical versus thalamic processing is coor- differentially. This task effect was unrelated to motor processesdinated remain to be settled. We therefore aimed at specifying and emerged significantly prior at thalamic than at scalp level.respective activations during the performance of a go/no-go Amplitude fluctuations of depth and scalp responses showedtask. To this end, an electroencephalogram was recorded simul- site- and task-dependent correlations, particularly between thal-taneously from scalp and thalamic electrodes in seven patients amic and no-go-related activities at frontal recording sites. Weundergoing deep brain stimulation. Meanwhile, left- or right- conclude that an early classification of go and no-go instruc-directed precues were presented indicating with which index tions is performed already thalamically. It further appears thatfinger a button press should be putatively executed. Thereafter, this information is subsequently utilized by cortical areas en-2 sec elapsed until a go or no-go stimulus determined if the gaged in the definite inhibition of the prepared action. &INTRODUCTION cal regions (Behrens et al., 2003; also see Sherman &Human behavior has to be constantly aligned with novel Guillery, 1996 for a review). Indeed, different authors re-environmental conditions. One of the essential abilities ported on patients with thalamic infarctions, presentingto exert such executive control is the inhibition of con- with variable executive control dysfunctions (Van dertextually unsuited actions (see Smith & Jonides, 1999; Werf et al., 2003; Mennemeier, Fennell, Valenstein, &Norman & Shallice, 1986; Logan, 1985; Logan & Cowan, Heilman, 1992; Eslinger, Warner, Grattan, & Easton, 1991;1984 for reviews). Based on clinical observations in Sandson, Daffner, Carvalho, & Mesulam, 1991). Partic-brain-lesioned patients and on functional imaging stud- ularly concerning inhibitory control, functional imagingies, the processing of such adaptive functions is mostly studies demonstrated thalamic next to prefrontal activa-allocated to frontal areas, in particular, the dorsolateral tions when prepared motor responses had to be sup-prefrontal and anterior cingulate cortices (Carter et al., pressed (de Jong & Paans, 2007; Garavan, Ross, Murphy,1998; D’Esposito et al., 1995; Petrides, Alivisatos, Meyer, Roche, & Stein, 2002). However, as functional imaging& Evans, 1993; Shallice & Burgess, 1991; Pardo, Pardo, hardly specifies the timing of rapidly changing activa-Janer, & Raichle, 1990). tions across different brain areas, it cannot be said how With the spread of neuroanatomical models on cortico- and in which position the thalamus is involved in suchbasal connectivity (see Alexander, Crutcher, & DeLong, operations.1990 for a review), respective research questions addi- Exceptionally, this issue can be addressed by electro-tionally focused on the impact of subcortical structures encephalography (EEG), if conventional scalp recordingson diverse higher-order operations (Rieger, Gauggel, are combined with derivations from thalamic electrodes,& Burmeister, 2003; Kramer, Reed, Mungas, Weiner, & for instance, in patients with deep brain stimulation (DBS;Chui, 2002; Rafal & Posner, 1987; also see Basso, Uhlrich, Kuhn et al., 2004; Foffani et al., 2003; Marsden, Ashby,& Bickford, 2005; Heyder, Suchan, & Daum, 2004; Royall Limousin-Dowsey, Rothwell, & Brown, 2000). Intriguingly,et al., 2002 for reviews). In this regard, the human thal- this approach combines the high temporal resolution ofamus appears in a strategically critical position for its EEG with otherwise inaccessible spatial information. Ofextensive reciprocal connections with almost all corti- note in the present context, simultaneous recordings from the scalp and the ventral intermediate nucleus (VIM) of the thalamus have recently been performed in DBS pa-Charite—University Medicine Berlin ´ tients, who engaged in a classical oddball task. The mostD 2008 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 20:10, pp. 1903–1914
  2. 2. unexpected finding of this study was that thalamic event- in VIM. At this time, patients were without medicationrelated potentials (ERPs), differentially expressed upon and almost tremor-free due to the short-lived post-target stimuli, emerged prior to analog ERPs at scalp level operative microthalamotomy effect (Kondziolka & Lee,(Klostermann et al., 2006), suggestive of a central role of 2004).thalamic processes in attentive behavior. The externalization phase serves to confirm the cor- The timing of thalamic versus cortical operations re- rect electrode localization by MRI (which cannot be per-lated to executive control has not been studied so far. formed with the implanted stimulator) and to assess theWe therefore recorded EEGs simultaneously from scalp (side) effects of DBS by a disconnectable external testand thalamic electrodes in a number of DBS patients stimulator, so that unfavorable electrode placementsengaging in a go/no-go task. They had to execute versus could be corrected at this stage (no revisions necessaryinhibit previously cued finger movements. Go versus in the present group). After this test phase, the definiteno-go instructions are known to elicit differential ERPs, DBS stimulator is implanted in the subclavicular regionreflecting the time course of activations due to response and subcutaneously connected with the electrode leadsinhibition in fronto-cortically assumed areas (Bokura, (making electrode revisions thereafter more complex).Yamaguchi, & Kobayashi, 2001; Kiefer, Marzinzik, Weisbrod, From this programmable stimulator, high-frequencyScherg, & Spitzer, 1998; Strik, Fallgatter, Brandeis, & electrical impulses are continuously delivered to thePascual-Marqui, 1998). These go- and no-go-related scalp electrodes, modulating the function of the target arearesponses were used as a reference for the simulta- which, in the case of tremor, is VIM (Schuurman et al.,neously recorded thalamic ERPs. Thus, task-related am- 2000). Accordingly, ET was strongly reduced by VIM DBSplitude and timing differences could be assessed for in the present group (tremor scores without/with DBS:scalp versus thalamic sites in order to analyze how pro- 3.1 ± 0.3/0.7 ± 0.7; 0 = absent; 1 = mild, intermittent;cesses at either level related to response inhibition as a 2 = moderate; 3 = markedly abnormal, interfering withbasic function of executive control. many activities; 4 = severely abnormal, interfering with most activities; scale according to Fahn et al., 1993).METHODSSubjects Visual Go/No-go taskSeven patients (2 women, 5 men; 36–74 years) with es- Three hundred sixty visual trials were presented persential tremor (ET) participated in this study. They were patient. Each trial was initiated by the presentation ofcognitively unimpaired (Mini-Mental State: 29 ± 1.3 a warning cue for 200 msec, either as an arrow directedout of 30 points, range 27–30, cutoff for suspected de- to the left or to the right. The direction of arrows indi-mentia 23; Fillenbaum, Heyman, Williams, Prosnitz, & cated with which index finger a motor response shouldBurchett, 1990) and had normal presurgical magnetic be prepared (Figure 1). After 1800 msec, the imperativeresonance imaging (MRI) scans. They underwent thera- cue appeared for further 200 msec, either as a go cuepeutic DBS of the thalamic VIM, known to suppress ET (green square), upon which the prepared movementeffectively (Schuurman et al., 2000). All patients gave had to be executed, or as a no-go cue (red square),informed consent to the study protocol, which was ap- upon which it had to be withheld. Left versus right di-proved by the local Ethics Committee. rected arrows and green versus red squares, respec- During the first days after DBS electrode placement tively, occurred with probabilities of 50%. The resulting(Day 4.1 ± 1), the patients engaged in a go/no-go task, four conditions ‘‘left-go,’’ ‘‘right-go,’’ ‘‘left-no-go,’’ andwhile a scalp EEG was performed together with record- ‘‘right-no-go’’ appeared in randomized order, each com-ings from the externalized leads of the DBS electrodes prising 90 trials.Figure 1. Go/no-go paradigm.Each task trial consistedof the presentation of aside-instructive precuefollowed by either a go orno-go instruction. Left- versusright-directed instructionsand go versus no-go signalsappeared equiprobably inrandomized order. The 360trials per session appearedat intervals of 4 sec.1904 Journal of Cognitive Neuroscience Volume 20, Number 10
  3. 3. All stimuli popped up within a 5 Â 5-cm2 frame, cen- bipolar derivations of 4.5 mm (1–3) and 7.5 mm widthtered in the middle of a 15-in. computer screen and (0–3), respectively (cf. Figure 2). By subtraction of De-present during the entire presentation time. The pa- rivation 1–3 from Derivation 0–3, the upper 4.5 mm oftients, sitting at 1.5 m distance, were instructed to look the recording trajectory could be differentiated fromat this frame also in-between trials (intertrial interval = the residual lower 3 mm, as the difference signal ap-1800 msec) in order to avoid EEG artifacts from gross proximates the physical bipolar derivation over thiseye movements. caudal portion. This partitioning was done as the ori- gins of task effects could thus be estimated. First, if an effect was obtained only in one of the two recordingThalamic Recordings regions, a generation near to the sensitive derivationElectrodes were implanted bilaterally into the VIM could be assumed (otherwise, the effect should project(Medtronic electrode 3387). For electrode placement, into the upper and lower derivation, covering adjacentstandard VIM positions from the stereotactic brain atlas areas of few millimeters along the same trajectory).by Schaltenbrand and Wahren (1977) were referred to Second, the lowest contact was targeted to the cau-the individual AC–PC line (the straight sagittal connec- dal border of VIM, which demarcates this nucleus totion between the anterior and posterior commissures), nonthalamic structures, namely, the Zona incerta. Con-exactly identified by intraoperative ventriculography. trarily, at its posterior, anterior, cranial, and medialStandard coordinates were adjusted for each case with limits, VIM is surrounded by further thalamic nuclei.respect to the individual thalamic height (15.3 ± 1 mm) Thus, effects generated in subthalamic regions adjacentand AC–PC length (24.8 ± 1.5 mm), determined by to VIM should, first of all, project into the lower deriva-matching presurgical stereotactic MRI with ventriculo- tion, whereas processes, generated more centrally in thegraphic data. The thus-calculated coordinates for the thalamus, will rather become discernible in the upperlowest contact of the right/left VIM electrode (see be- derivation.low), expressed as (i) anteriority to PC, (ii) lateralityto AC–PC, and (iii) verticality to AC–PC, were: (i) 7.2 + Surface Recordings0.4 mm/7 + 0.5 mm, (ii) 14.6 + 0.5 mm/14.5 + 0.5 mm,and (iii) À0.1 + 0.4 mm/À0.2 + 0.6 mm (minus in- Scalp electrodes (Neuroscan system) were positioneddicating below AC–PC). Postsurgical MRI confirmed at F3, Fz, F4, C3, Cz, C4, P3, Pz, and P4 according tothat the planned placements were met by the implanted the 10–20 system (impedances <5 k) and referencedelectrodes. to linked mastoid electrodes. By this array, the typical DBS electrodes consist of four ring contacts (0–3 from spatio-temporal distribution of fronto-central P300 re-basal to cranial), longitudinally spaced at distances of sponses upon go versus no-go stimuli could be con-1.5 mm in VIM implants. On both recording sides, Con- firmed per patient. It was expected that the ‘‘no-gotacts 0 and 1 were referenced to Contact 3, resulting in P300’’ would peak over frontal scalp sites upon theFigure 2. Simultaneous scalpand thalamic recordings.Scalp EEG was derivedsimultaneously with depthrecordings from the thalamicventral intermediate nucleus(VIM; n = 14) in a group oftremor patients. The MRIsshow representative DBSelectrode positions in onepatient. Two bipolar channelscovered the lower (light field)and upper (dark field) portionsof the DBS electrodes, thecircles representing thestereotactically defined edgesof these adjacent channelsper patient. The projectionof the recording fields onthe 13-mm paramedian slicefrom the Schaltenbrand atlassuggests that depth samplingareas were at the loweredge and well within VIM,respectively. Marzinzik et al. 1905
  4. 4. instruction to withhold a prepared movement. This ERP peak. At scalp level, this procedure referred to the maxi-component is a positive potential in the time window mum component between 300 and 600 msec, a timebetween 300 and 600 msec upon no-go signals and is of domain in which ERPs upon go and no-go signals beganmarkedly larger magnitude than the according ERPs in to differ and which is typical of P300 responses elicitedthe go condition ( Weisbrod, Kiefer, Marzinzik, & Spitzer, in comparable paradigms. At thalamic level, latency and2000; Roberts, Rau, Lutzenberger, & Birbaumer, 1994; amplitude values were assessed for the first component,Eimer, 1993; Jodo & Inoue, 1990; Pfefferbaum & Ford, which was differentially expressed between go and1988; Pfefferbaum, Ford, Weller, & Kopell, 1985; Simson, no-go conditions.Vaughan, & Ritter, 1977). The origin of the no-go P300 The main statistical analysis primarily aimed at iden-is allocated to prefrontal and cingulate cortical areas tifying factors for the amplitude and latency values of(Kiefer et al., 1998). Thus, the time course of cortical scalp and thalamic ERPs. Therefore, three-way analysesactivations related to response inhibition can be delin- of variance (ANOVAs), with the test factors task con-eated by comparing the respective ERPs in the go versus dition (two levels: go/no-go), response side (two levels:no-go condition. left/right), and electrode position, were performed, sep- Thalamic and scalp data were sampled continuously arately for the scalp (nine levels: F3/Fz/F4/C3/Cz/C4/P3/at 2 kHz with a bandpass from 0.05–500 Hz. Horizontal Pz/P4) and the thalamus (four levels: lower left, upperand vertical electrooculogram were registered to screen left, lower right, upper right).against eye-blink artifacts. Further, in order to compare go/no-go-related ERPs at scalp versus thalamic level chronometrically, the peak latencies determined at the electrode positions with theAnalysis largest amplitude effect for task condition (i) at scalpPeristimulus EEG segments from À200 to +1000 msec level and (ii) at thalamic level were utilized for a furtherwere averaged separately over left-go, right-go, left-no-go, three-way ANOVA. This ANOVA comprised the test fac-and right-no-go trials, unless they were handled incor- tors task condition (two levels: go/no-go), response siderectly or contained eye-blink artifacts. Further, averages (two levels: left/right), and brain level (two levels: elec-were calculated relative to the reaction times (button trode positions at which the effect of task condition onpresses) in the go condition. Thus, back averages from ERP amplitudes was strongest (i) at scalp level and (ii)the motor response could be compared to the stimulus- at thalamic level). As post hoc comparisons, Newman–triggered forward averages, determining if a component Keuls tests were performed.reflected predominantly sensory or motor processes. If scalp and thalamic ERPs had different peak laten- To assess if minor activity discernible in the back cies, the onset of the target effect was additionally de-average was the residual of sensory components in the termined. Therefore, no-go ERPs were subtracted fromforward average or were proper motor potentials, an go ERPs at either level to better display the time courseadditional analysis was performed. Per patient, the re- of differences between conditions. The task effect wasaction times from the go trials were marked down to considered to start out with the first poststimulus inter-the no-go trials which, on this basis, could be averaged val of at least 25 msec, in which the averaged amplitudesin the very same way as the go trials. Such ‘‘sham aver- exceeded the standard deviation across baseline valuesages’’ in the no-go condition (not containing any motor by a factor > 2. Statistically, this was assessed with run-responses) were individually compared with the back ning t tests based on moving averages over 50 dataaverages (based on reaction times). Activity in the back points per patient.average was considered a correlate of motor processing If task effects were proven at both thalamic and scalpif it exceeded according activity in the sham average, sites, it was further tested if these effects were correlatedwhereas it was viewed the residual of sensory compo- between the different recording levels, putatively indic-nents if it was identically identified in the sham average. ative of thalamo-cortical networks active in executive Analysis of scalp and thalamic data was performed at control. Therefore, per patient three subaverages, eachoff-line filter settings from 0.5 to 20 Hz and from 20 to over one third of the artifact-free and correct left- and50 Hz. The former bandpass was chosen with respect to right-hand go as well as no-go trials (each containing atthe main spectral energy of P300 components between least 20 trials), were built, reflecting the ERP fluctuations5 and 10 Hz in line with conventional methodology, over subsequent time segments of the recording sessionthe latter was additionally applied as phase-locked tha- in either task condition. For the resulting (sub-)ERPs,lamic activity has hardly been described and might the amplitude values of the monophasic thalamic com-exceed the spectrum known from scalp ERPs, so that po- ponent, differentially expressed between go and no-gotentially faster components would not escape this scru- condition (cf. Results), were then matched with the am-tiny. Latency values were determined from the point in plitude values of the first component in the time domaintime at which the stimulus was delivered to the peak of of the task effect assessed at all scalp electrode sites.a component. Amplitudes were measured from baseline For the interindividual comparability of the results, mag-(defined over the 200 msec prestimulus interval) to nitudes were expressed in proportion to the mean of1906 Journal of Cognitive Neuroscience Volume 20, Number 10
  5. 5. the three amplitudes determined per subject, condition, nitudes at scalp and thalamic levels. This differenceand recording site normalized to 1. In so doing, a between ‘‘forward’’ versus ‘‘back’’ averages suggestsPearson’s coefficient of correlation could be determined that the described components predominantly reflectacross subjects for each thalamo-cortical electrode pair the processing of go and no-go stimuli rather than the[per condition: 3 (subaverages)  2 (left/right response motor execution of the task. This was corroborated byside)  7 (subjects)]. Thus, it could be assessed if ERPs the comparison of the ‘‘back averages’’ of the go trialsin the go and no-go condition covaried between depth with the ‘‘sham averages’’ of the no-go trials (replicatingand scalp recording sites or, alternatively, behaved inde- the time criteria in the back averages; for details, cf.pendently from each other and, secondly, how putative under Methods, Analysis). In the sham averages, thethalamo-cortical relations were spatially distributed. residual activity from scalp as well thalamic components upon the no-go signal was undistinguishable from the activity obtained in the back average of the go trials (Figure 5). Thus, during the time domain of interest, theRESULTS attenuation of ERPs in both conditions was due to theOverview jitter of activity, phase-locked to go as well as no-go trialsPatients responded correctly to 88 ± 14%/98 ± 3% of and not to motor activity proper.go/no-go trials (difference of error rate not significant).The mean reaction time was slightly faster for right- thanleft-hand responses (596 ± 147 msec vs. 622 ± 178 msec; Amplitude Analysisdifference not significant). Generally, ERPs were identified in the data filtered Scalp ERPsfrom 0.5 to 20 Hz and were absent above this frequency An interaction Task condition  Electrode position wasband, regardless of the recording site. At scalp level, found [F(8, 48) = 12.85, p < .0001] according to thepositive scalp ERPs upon go as no-go stimuli peaked be- observation that P300 components were larger upontween 300 and 600 msec at all recording sites, according no-go stimuli than upon go stimuli at rostral recordingto typical P300 responses. At parietal sites, the P300 am- sites. Post hoc comparisons proved the difference be-plitudes and latencies in the go condition were similar to tween ERP magnitudes of either condition to be sig-those in the no-go condition. At fronto-central positions, nificant at all frontal and central positions but strongestP300 components upon no-go stimuli were, however, at Fz ( p < .001). The effect was not modulated by thelarger and occurred later than upon go stimuli. In tha- response side.lamic recordings, monophasic ERP components wereidentified upon either stimulus class at almost identical Thalamic ERPslatencies around 280 msec. This component, which pre-ceded the fronto-central P300, was found larger upon According to the observation that go stimuli elicited largergo than upon no-go stimuli (cf. Table 1 and Figure 3). ERPs than no-go stimuli in thalamic recordings, task con-Further, upon go instructions, differences due to the dition was shown a main effect [F(1, 6) = 8.45, p < .028].laterality of the executed response emerged only after The interaction Task condition  Electrode position [F(3,the peak of this thalamic component (cf. Figure 4). 18) = 4.12, p < .022] was due to the fact that a significant Averaging with respect to the motor response (go difference between go- and no-go-related ERPs was onlycondition), resulted in a strong attenuation of ERP mag- obtained at the upper portion of the DBS electrode, butTable 1. Latencies and Amplitudes of ERP upon Go and No-go Stimuli Thalamus Scalp (P300)Stimulus Left Right F3 Fz F4 C3 Cz C4 P3 Pz P4Peak Latencies (msec)Go 278 ± 11 280 ± 15 410 ± 19 412 ± 17 413 ± 16 413 ± 16 411 ± 16 411 ± 16 412 ± 13 412 ± 13 407 ± 14No-go 281 ± 12 272 ± 10 465 ± 16 471 ± 20 470 ± 20 472 ± 20 459 ± 27 467 ± 18 446 ± 15 436 ± 21 426 ± 23Amplitudes (V)Go 6.5 ± 1.4 5.7 ± 0.9 2.9 ± 0.9 3.4 ± 1 3.8 ± 0.9 4.5 ± 1.1 4.5 ± 1.3 5.2 ± 1.2 5.6 ± 1.4 6.6 ± 1.3 6.1 ± 1.2No-go 4.1 ± 0.9 3 ± 0.5 6.4 ± 1 7.1 ± 1.1 6.8 ± 1.1 7 ± 1.6 7 ± 1.1 7.2 ± 1.3 6.3 ± 1.2 6.8 ± 1.3 6 ± 1.1Peak latencies (± standard error) and amplitudes (± standard error) of thalamic (upper channel) and scalp ERPs. Marzinzik et al. 1907
  6. 6. Figure 3. Distribution of scalp and thalamic go and no-go ERPs. Overview of grand-averaged frontal, central, and parietal (A) as well as thalamic(B) ERPs, averaged over ipsilateral and contralateral responses. The ERPs upon the go signal are indicated by the dashed line, the ones uponthe no-go signal by the solid line. The scalp no-go P300 peaked later than the thalamic ERPs following go and no-go signals.not at its lower part (post hoc tests for upper/lower chan- that P300 components upon no-go stimuli peaked signif-nels: p .05/p .3). No further interactions were found. icantly later than upon go stimuli only at frontal and cen- tral recording positions, this effect being strongest at Fz ( p .001).Latency AnalysisScalp ERPs Thalamic ERPsTask condition was shown a main factor [F(1, 5) = 8.32,p .034], further interacting with electrode position [F(8, The monophasic thalamic ERPs upon go versus no-go40) = 2.29, p .041]. The post hoc comparisons revealed stimuli did not differ in latency.1908 Journal of Cognitive Neuroscience Volume 20, Number 10
  7. 7. Figure 4. Thalamic ERPs in left-hand versus right-hand conditions. The amplitude of the thalamic components at peak latency was not influencedby the side of motor execution: (A) The upper traces show the lateralization of thalamic ERP upon go instructions, compared for left-hand(dotted line) versus right-hand (solid line) responses. Side-related differences emerged only after the peak of the monophasic thalamic ERPs.(B) Upon no-go instructions, no lateralization was obtained.Chronometric Comparison of the Thalamic more than 2 standard deviations excess from baselineand Scalp ERPs noise, as determined in the 200-msec interval before sig- nal presentation; cf. Methods, cf. Figure 6).Brain level was a main factor of peak latencies in tha-lamic versus scalp ERPs based on the recording positionsdisplaying the strongest task effects on ERP amplitudes Correlation between Thalamic and Scalp ERPsof either level [left/right thalamus vs. Fz: F(1, 6) = 85.98/76.09, p .0001]. Further, task condition was a cofactor Thalamic and scalp ERPs were correlated with respect to[Brain level  Task condition for left/right thalamus vs. the amplitude fluctuations along the recording sessionFz: F(1, 6) = 9.01/8.45, p .024/ .027], according to (see Methods), but this thalamo-cortical correlation wasthe fact that P300 components at Fz peaked later upon spatially distinct for go versus no-go ERPs. Specifically,no-go than upon go stimuli ( p .01), whereas thalamic thalamic no-go ERPs behaved similarly to accompanyingERP latencies were similar in the go and no-go condi- ERPs in the time domain of the task effect at frontal sites,tion. Thalamic ERPs, in turn, peaked prior to scalp P300 where the no-go effect was largest. No such relation wascomponents both in the go and no-go condition ( p obtained for go ERPs which, instead, mostly correlated to.001/p .001). the according parietal ERPs (for summary, see Table 2). Accordingly, the onset of the task effect was deter-mined earlier in thalamic than in scalp ERPs ( p .0001).In the subtraction curves of go versus no-go ERPs, it was DISCUSSIONdetermined to start at 196 ± 27 msec and 296 ± 57 msecafter signal presentation for thalamic ERPs and scalp The present study contained three major findings. First,ERPs at Fz, respectively (criterion: during 25 msec as at fronto-central scalp sites, ERPs recorded from the Marzinzik et al. 1909
  8. 8. Figure 5. Nonmotor character of frontal and thalamic go/no-go ERP. (A) The upper traces show scalp and thalamic ERPs to go/no-go stimuli,contralateral to task execution/instruction, averaged to stimulus presentation (forward average). (B) The lower traces display the ERPs, averagedwith respect to the motor execution of the task for the go condition (back average; dashed line) and an according ‘‘sham ERP’’ for the no-gocondition (solid line). For the latter, the reaction times from the go trials were marked down to the no-go trials. Thus, no-go trials could beaveraged in the very same way as the go trials, although they did not contain any motor response. As activity in the back average was foundlargely identical with that in the sham average, it was viewed the residual of the sensory components discernible in the forward average.Figure 6. Difference curves(go minus no-go condition) forscalp and thalamic ERPs. Thetask effect is shown as thedifference of ERPs in the goversus no-go condition at scalpand thalamic levels (grandaverage). The beginning ofthis effect was calculated perpatient as the first poststimulusinterval of at least 25 msecexceeding the standarddeviation across the individualbaseline values by morethan a factor of 2. Thethus-determined onsets weresignificantly earlier in thalamiccompared to scalp recordingsand are indicated by thesolid and dashed arrows,respectively.1910 Journal of Cognitive Neuroscience Volume 20, Number 10
  9. 9. Table 2. Co-fluctuations of Thalamic and Scalp ERP Amplitudes Go Condition No-go ConditionScalp Left Thalamus Right Thalamus Left Thalamus Right ThalamusF3 r = .17 ( p .29) r = .13 ( p .42) r = .75**(p .001) r = .76** (p .001)Fz r = .19 ( p .22) r = .19 ( p .23) r = .76** (p .001) r = .75** (p .001)F4 r = .13 ( p .39) r = .23 ( p .15) r = .76** (p .001) r = .90** (p .001)C3 r = .43** (p .005) r = .33* (p .05) r = .58** (p .001) r = .74** (p .001)Cz r = .34* (p .03) r = .15 ( p .33) r = .24 ( p .12) r = .26 ( p .11)C4 r = .35* (p .05) r = .45** (p .01) r = .18 ( p .26) r = .29 ( p .06)P3 r = .45** (p .01) r = .45** (p .01) r = À.17 ( p .28) r = À.22 ( p .17)Pz r = .52** (p .001) r = .55** (p .001) r = .07 ( p .65) r = .09 ( p .58)P4 r = .49** (p .001) r = .57** (p .001) r = À.22 ( p .15) r = À.06 ( p .70)r = Pearson’s correlation coefficient.*Significant at .05 level.**Significant at .01 level (two-tailed; cf. Methods).upper intrathalamic electrode were differentially ex- of control processes exclusively refer to the cortical level,pressed upon no-go versus go commands, and this dif- based on scalp ERPs. In this particular context, the re-ference was not explained by motor processing. Second, ported depth ERPs merit a closer view.whereas thalamic ERPs correlated to the parietal P300component in the go condition, they corresponded to Origin of VIM-recorded ERPsthe task-specific frontal ERP component in the no-gocondition. Third, task-specific scalp components started An intrathalamic origin of VIM-recorded ERPs can bewell after thalamic go as well as no-go ERPs. reasonably assumed for several reasons. First, if depth signals were volume conducted from cortical generators, time courses of components at scalp and thalamic levelsRelation to Previous Studies should be synchronous. Accordingly, the discrepant la-Worthwhile mentioning, the obtained spatio-temporal tencies of scalp versus VIM ERPs point to a closer, that is,pattern of scalp ERPs was as described in numerous subcortical, origin of the latter. Second, the upper, butstudies applying comparable paradigms. Specifically, the not the lower, derivation from DBS electrodes caughtfrontal component under scrutiny, often labeled ‘‘no-go significant differences between go and no-go-relatedP300,’’ has been conceptualized as the reflection of ag- ERPs. This disparity points to an effect from near-fieldgregate activity for the suppression of actions, according activities. Far-field spread would almost equally projectto its enhancement in no-go trials (Roberts et al., 1994; into upper and lower derivation because of similar rela-Eimer, 1993). The recording array used in this study does tive positions to both recording fields, covering few adja-not allow to deduce the origin of this component, but cent millimeters along the same trajectory only. Finally,previous studies focused on this issue. Based on source the absence of a the task effect in the lower thalamicanalysis of frontal P300, the provision of assigned func- derivations suggests that its proof in the upper record-tions has been allocated to the anterior cingulum, the ings was due to processes in proximate thalamic struc-prefrontal cortex, and the premotor cortex (Kamarajan tures, and not to operations in nuclei adjacent to theet al., 2005; Bokura et al., 2001; Kiefer et al., 1998; Strik caudal border of VIM outside the thalamus. However, anet al., 1998). Accordingly, executive control operations origin in VIM proper seems unlikely, as both the upperwere proposed to be generated in a frontal lobe network, and lower depth recording areas were estimated to bealthough a number of imaging studies and reports on predominantly within this nucleus.patients with subcortical lesions point to an additionalinvolvement of thalamic structures (Van der Werf et al., Nonmotor Nature of Thalamically Recorded ERPs2003; Garavan et al., 2002; Mennemeier et al., 1992;Eslinger et al., 1991; also see Van der Werf, Witter, Several results indicate that the thalamic activation inUylings, Jolles, 2000, for a review). However, a more the time domain of interest is unrelated to proper motorspecific assignment of according subcortical functions is operations. First, thalamic ERPs in trials with left- versusnot available so far, and estimations on the chronometry right-sided motor responses did not differ in magnitude Marzinzik et al. 1911
  10. 10. at their peak latencies. Such a difference could be rea- demands, appear aligned with more frontally locatedsonably assumed if this component reflected primary areas than throughout facilitatory processing, compati-motor processes, as observed in later time domains of ble with a particular involvement of dorsolateral prefron-the ERPs. Second, thalamic ERPs were bound to stimulus tal and anterior cingulate cortices in executive controlpresentation rather than to the motor execution of the (Carter et al., 1998; D’Esposito et al., 1995; Petrides et al.,task, as they occurred upon go and no-go trials, al- 1993; Shallice Burgess, 1991; Pardo et al., 1990).though in the latter motor responses were not executed. Such selective coupling might be a function of thalamo-Third, a predominant binding of the ERPs to motor exe- cortical, together with thalamic reticular neurons, whosecution was incompatible with the finding that they were firing properties and connectivity provide a mechanismmassively reduced in magnitude when averaged to the for scaling and funneling information through the wide-motor response as compared to the go instruction. spread thalamic connections to frontal and temporo-Fourth, the larger amplitude obtained in go versus no- parietal cortical regions (Behrens et al., 2003; Shermango conditions could finally not be explained by additive Guillery, 1996; Crick, 1984; see also Pinault, 2004;motor operations. This was shown by the comparison of Guillery Sherman, 2002a, 2002b for reviews).ERPs in go trials, averaged to the motor response, versus Intriguingly, the chronometric comparison of thalamicERPs in no-go trials, averaged to the very same points and scalp ERPs suggested that task-specific informationin time (‘‘sham average’’; cf. Methods and Results). In was propagated in thalamo-cortical direction, that is, noso doing, activations in the critical interval became un- indication was found that the underlying thalamic pro-distinguishable between conditions, delineating that the cesses occurred under the control of related corticaladded thalamic activity was due to the go instruction areas. This, together with the possibility of a thalamicallyproper, but not to its execution. induced cortical coupling of go versus no-go-related signaling, can be viewed as an experimental parallel to ‘‘centrencephalic’’ concepts, derived from the PenfieldConceptual Considerations and Jasper (1954) formulation that a subcortical struc-In this context, a number of proposed thalamic func- ture can be ‘‘while anatomically subcortical, functionallytions are of particular interest. During attentional and supra-cortical,’’ further relating to the principle questionarousal processes, activation has been described for in- if qualia can exist if subcortical structures work withouttralaminar thalamic regions (Fan, McCandliss, Fossella, a corresponding cortex (cf. Merker, 2007; Schiff et al.,Flombaum, Posner, 2005; Hester, Fassbender, 2007).Garavan, 2004; Woldorff et al., 2004; Garavan et al., The task-dependent expression of thalamic ERPs calls2002; Portas et al., 1998; Coull, Frith, Dolan, Frackowiak, for the comparison with previous results. Both go and Grasby, 1997; Frith Friston, 1996), which receive no-go instructions require specific performances withafferent connections from the midbrain reticular forma- respect to previously established expectancies. There-tion and project to multiple cortical areas (McFarland fore, their magnitudes do not appear to reflect thalamicHaber, 2002; Macchi, Bentivoglio, Molinari, Minciacchi, weighing of signal relevance, given that both go and1984; Steriade Glenn, 1982; Bentivoglio, Macchi, no-go signals convey behaviorally important informa-Albanese, 1981; also see Merker, 2007; Jones, 1998 for tion. In this sense, go and no-go signals are compara-reviews). It has been hypothesized that midbrain signals ble to target signals in oddball paradigms. Interestingly,convey stimulus-related alert or orienting information in a recent study, oddball target signals, rarely inter-to the thalamus (Kinomura, Larsson, Gulyas, Roland, spersed between nontarget instructions, led to consid-1996), which in turn communicates with specific cortical erably larger thalamic ERPs than the present go andregions, depending on the ongoing behavioral demands no-go instructions (cf. Klostermann et al., 2006). There-(see Merker, 2007; Pinault, 2004 for reviews). Similarly, fore, our momentary working hypothesis is that theit has been suggested that sensorily driven bottom–up mentioned thalamic ERPs reflect distinct (rather thansignals are integrated with top–down directed informa- unitary, but weighed) aggregate activities whose com-tion in the center median and parafascicular nuclei of the position imply variable thalamic contributions, specifi-thalamus (reviewed by Sarter, Givens, Bruno, 2001; cally defined by the given behavioral context. However,LaBerge, 1997). the verification of this and the critical questions how and Of course, from the present data, any brainstem con- by what task definitions are imposed upon the thalamustributions to the results remain speculative, but the cor- remain central issues for future studies.relations between thalamic and scalp ERPs do hint atdifferential thalamo-cortical processing. According in- Conclusionsteractions appeared task-dependent, as in the no-gocondition, thalamic ERPs co-fluctuated with the frontal Principally, the distinct expression of thalamic ERPs uponno-go P300, whereas in the go condition, they mainly did go versus no-go instructions indicates thalamic involve-so with the parietal P300. This seems to imply thalamo- ment in executive control. Further, the fact that task-cortical routes of information which, in case of inhibitory specific activity emerged prior in depth recordings than1912 Journal of Cognitive Neuroscience Volume 20, Number 10
  11. 11. at scalp level suggests cortical operations of response Fan, J., McCandliss, B. D., Fossella, J., Flombaum, J. I.,control to be subcortically prepared. Finally, the corre- Posner, M. I. (2005). The activation of attentional networks. Neuroimage, 26, 471–479.lation of thalamic to frontal ERPs in the no-go condition Fillenbaum, G., Heyman, A., Williams, K., Prosnitz, B.,and of thalamic to parietal ERPs in the go condition in- Burchett, B. (1990). Sensitivity and specificity ofdicates that the underlying thalamo-cortical networks are standardized screens of cognitive impairment andflexibly activated as a function of task demands. dementia among elderly black and white community residents. Journal of Clinical Epidemiology, 43, 651–660. Foffani, G., Priori, A., Egidi, M., Rampini, P., Tamma, F.,Acknowledgments Caputo, E., et al. (2003). 300-Hz subthalamic oscillations in Parkinson’s disease. Brain, 126, 2153–2163.This study was supported by the Deutsche Forschungsgemein- Frith, C. D., Friston, K. J. (1996). The role of the thalamusschaft (DFG KL 1276/3-1). We thank our reviewers for their in ‘‘top down’’ modulation of attention to sound.constructive suggestions and comments. Neuroimage, 4, 210–215.Reprint requests should be sent to Fabian Klostermann, Garavan, H., Ross, T. J., Murphy, K., Roche, R. A., Stein,Neurology, Charite—University Medicine Berlin, Campus ´ E. A. (2002). Dissociable executive functions in theBenjamin Franklin, Berlin, 12200, Germany, or via e-mail: dynamic control of behavior: Inhibition, error detection,fabian.klostermann@charite.de. and correction. Neuroimage, 17, 1820–1829. Guillery, R. W., Sherman, S. M. (2002a). Thalamic relay functions and their role in corticocortical communication:REFERENCES Generalizations from the visual system. Neuron, 33, 163–175.Alexander, G. E., Crutcher, M. D., DeLong, M. R. (1990). Guillery, R. W., Sherman, S. M. 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