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Although the descending projection from the primarysomatosensory cortex to the ventroposterior nucleus (VP) of thethalamus is known to be seven to ten times greater than theascending projection from VP to cortex1, the functional role ofthis massive corticofugal projection has remained elusive2. Pre-vious studies on the contribution of neural feedback connectionsto the processing of sensory information have reported relative-ly minor and inconsistent effects on receptive field size orresponse properties of thalamic relay neurons following corticalperturbations3–7. Although the connectivity of the system sug-gests a substantial influence from cortex over the processing ofsomatosensory information at the level of the thalamus, therehas been no definitive demonstration of a major cortical influ-ence on receptive field size, response properties or somatotopicorganization in VP.

A majority of corticofugal projection cells in primarysomatosensory cortex (area 3b) express NMDA receptors8, andchronic systemic blockade of NMDA receptors produces largeunresponsive areas in somatosensory cortex9. In this study, wedetermined that chronic administration of an NMDA receptorantagonist directly into the area 3b cortical hand representa-tion results in a suppression of activity in area 3b and an enor-mous enlargement of receptive fields (RFs) in the VP handrepresentation. In addition, acute cortical suppression alsoresulted in an enlargement of RFs in VP. These findings force are-evaluation of traditional ‘bottom-up’ models of sensory pro-cessing, which view the thalamus as a simple relay nucleus tothe cortex, and they also have important implications for stud-ies of adult neuronal plasticity.

ResultsOver a period of one to five months, either saline (two controlmonkeys, Macaca mulatta) or the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (D-APV; five monkeys, Maca-ca mulatta) was infused directly into the area 3b handrepresentation. The percentage of responsive sites and RF size forthe cortex and VP in the saline control group was completely

consistent with those reported in previous studies by us and oth-ers in normal animals10–12. In accordance with previous stud-ies9, our recordings throughout the cortical hand representationone to five months after D-APV administration revealed thatonly 10% of cortical recording sites were responsive to somaticstimulation (Table 1), compared to 100% in control animals.Analysis of the responsive 10% of recording sites in the cortex ofthe experimental animals showed that these neurons exhibitedRFs comparable in size to those found in the cortex of the controlanimals. There was no evidence of degeneration in the thalamusor cortex in any of the animals used in the present study.

These results on RF size obtained at the cortical level in thechronic D-APV treated animals contrasted sharply with thosefound at the thalamic level of these same animals, where RFswere greatly enlarged compared to those seen in controls, fre-quently encompassing more than one digit and often half ormore of the entire glabrous hand (Fig. 1c). In some instances

Cortically induced thalamic plasticity inthe primate somatosensory system

E.R. Ergenzinger1,2, M.M. Glasier1, J.O. Hahm3 and T.P. Pons1

1 Department of Neurosurgery and 2Program in Neuroscience, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27127, USA3 Department of Neurosurgery, Georgetown University, Washington, D.C. 20057, USA

Correspondence should be addressed to T.P.P. (tpons@wfubmc.edu)

The influence of cortical feedback on receptive field organization in the thalamus was assessed inthe primate somatosensory system. Chronic and acute suppression of neuronal activity in primarysomatosensory cortex resulted in a striking enlargement of receptive fields in the ventroposteriorthalamus. This finding demonstrates a dramatic ‘top-down’ influence of cortex on receptive fieldsize in the somatosensory thalamus. In addition, this result has important implications for studies ofadult neuronal plasticity because it indicates that changes in ‘higher-order’ areas of the brain cantrigger extensive changes in the receptive field characteristics of neurons located earlier in theprocessing pathway.

Table 1. Responsivity of recording sites in cortex andthalamus following chronic cortical administration of D-APV or saline1

Control D-APVCortex (Area 3b)% Responsive Sites

Infusion Zone (Hand) 100%(197) 10%(754)Other 100%(47) 99%(82)Fringe Zone (Hand & Other) N.A. 78%(262)

% “Large” RF Sites 0%(197) 6%(78)

Thalamus (VP)% Responsive Sites

Hand 100%(102) 99%(388)Other 99%(116) 100%(243)

% “Large” RF Sites 2%(102) 58%(383)

1see Methods for details on data analysis.

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these RFs included the entire distal forearm and hand (Fig. 1c), atype of RF that is never seen in normal animals. Such large RFswere recorded from 58% of the recording sites within the VPhand representation of our experimental animals. The RFenlargement was specific in that these RFs were observed onlyfor recording sites within the VP hand representation and not inbody-part representations outside of the D-APV infusion zonein cortex (Fig. 1c).

These findings indicate that chronic D-APV administrationin the area 3b hand representation blocks much of the stimulus-driven activity at the cortical level and tremendously expands thesize of RFs in the portion of the VP thalamus that normally rep-resents the hand (within the ventroposterior lateral nucleus orVPL). This expansion of RF size occurred for the vast majorityof hand-responsive recording sites throughout VPL (Fig. 2). Such

an enormous expansion of RF size after delivery of pharmaco-logical agents to either the cortex or thalamus has not beenreported previously3–7.

We next determined if acute administration of D-APV wouldproduce results similar to those from chronic treatment. We firstrecorded from the cortex and thalamus of two additional mon-keys before administering D-APV. We then delivered injectionsof D-APV directly to the cortex of these same animals via aHamilton syringe and immediately assessed the results. Acutecortical recordings were similar to those found in the chronical-ly administered animals, with 93% of 83 sites unresponsive tosomatic stimulation. Recordings in the thalamus of the acutelyadministered animals showed an increase in RF size, though notas great as that observed in the chronically administered animals.Although a comparable number of sites (45% of 55 sites) showedRFs that encompassed one or more digits, compared to only 2%of 51 sites before acute D-APV administration, the magnitudeof the RF enlargement was not as great as that observed in chron-ically administered animals, in that no RFs larger than half of thehand were observed (Fig. 3).

DiscussionThe present findings demonstrate that, at least under our exper-imental conditions, top-down projections from cortex can inducelarge-scale reorganization of RFs at a relatively early processingstation in the somatosensory system. This effect seems most like-ly to be mediated directly by corticothalamic projections or indi-rectly via corticocuneate projections. Additionally, the increasein RF size for VP neurons could occur through a loss of excita-tory corticothalamic input on inhibitory interneurons within VPor on the thalamic reticular nucleus. Of course, unknown changesin additional somatosensory cortical areas such as SII, the insu-la and/or posterior parietal cortex could conceivably mediate theRF enlargement through complex corticothalamic processing,though this latter possibility seems less likely. That these resultsmight be explained by retrograde degeneration seems highlyunlikely, given that lesions of the somatosensory cortex, whichare known to produce massive retrograde degeneration, do notresult in expanded thalamic RFs13. Furthermore, the expansion ofRF’s immediately after delivery of D-APV to the cortex would

Fig. 1. Representative RFs in VP following chronic administration of D-APV to somatosensory cortex. (a) Representative RFs, indicated bythinner black lines, recorded from sites localized within the hand region of VPL from saline controls. (b) Representative electrode tracksthrough a coronal section of the thalamus in a macaque that had received D-APV to the area 3b hand representation (CM, central median; LP,lateral posterior; VPM, ventroposterior medial; VPI, ventroposterior inferior; VPL, ventroposterior lateral). Tick marks on tracks indicaterecording sites. Red, recording sites with RFs on the face. Blue, recording sites with RFs on or including the hand. Green, recording sites withRFs on the forearm. Colors are matched with RFs in (c). (c) Representative RFs recorded from sites localized within VP from a monkey withD-APV administered to area 3b. All RFs were contralateral to VP. Arrow denotes rotation of the hand and forearm to allow visualization oftheir ventral surfaces.

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Fig. 2. Distribution histogram of RF sizes for recording sites local-ized within the VPL hand representation between control and D-APV groups. RFs were categorized as to whether they were ≤ 1 pad,< 1 digit, > 1 pad, or ≥ 1 digit. RFs that were classified as > 1 padwere restricted to the pads and did not encompass any digits of thehand. RFs that were classified as ≥ 1 digit were those RFs that incor-porated at least one digit, and included RFs as large as the entirehand and forearm (see Fig. 1).

ControlD-APV

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with an initial dose of ketaminehydrochloride (15 mg per kg) fol-lowed by intubation and admin-istration of isoflurane (0.5% to3%) to effect. Throughoutsurgery, which was performedusing aseptic precautions, the ani-mals received an intravenous dripof a solution of 5% dextrose and0.45% sodium chloride, and theirheart rate, respiratory rate, andtemperature were monitored andmaintained within normal limits.

For the chronic administrationof D-APV, we implanted a tran-scranial catheter directly into thehand representation in area 3b andattached the catheter to an osmot-ic pump containing 50 µM D-APVor physiological saline delivered ata rate of 2.5 µl per h. D-APV orsaline was administered from

between one and five months, and the osmotic pump was replaced every28 days. Ketamine was not used during osmotic pump replacements becauseof potential interactions with glutamatergic neurotransmission. Instead,valium was used to make the animal receptive to isoflurane anesthesia.

For the acute administration of D-APV, a Hamilton syringe was usedto inject D-APV directly into the hand representation in area 3b. In orderto assure that the entire hand representation was affected by the D-APVas in the chronic study, multiple injections of 2–3 µl of D-APV were madeapproximately 1 mm apart across the mediolateral extent of the handrepresentation in cortex (5–6 injections total). The injections consisted of50 µM D-APV.

ELECTROPHYSIOLOGICAL RECORDING PROCEDURES. A recording chamber andhead fixation device were attached to the skull. The chamber was madefrom dental acrylic and positioned to provide maximum access forrecording from VP and area 3b. The bone within the chamber wasremoved to expose the dura, the dura then reflected and a high resolu-tion picture of brain vasculature was then obtained with a CCD camerausing appropriate filters. The brain picture was used to help in the place-ment of electrode penetrations during recording, with the RF and respon-sivity characteristics defined for each recording point.

The mapping and recording procedures were similar to those usedpreviously25. In the chronic preparation, electrode penetrations wereplaced at 0.3–0.5 mm intervals across the mediolateral extent of VP andarea 3b and at 0.3–0.5 mm intervals across its rostrocaudal extent.Approximately 20–40 electrode penetrations were made across VP ineach hemisphere studied, and approximately 50–60 electrode penetra-tions were made through area 3b in each hemisphere studied. In the acutepreparation, 4–5 penetrations were made across VP, and 5–6 penetra-tions were made across area 3b before and after cortical D-APV injec-tions. Penetrations across VP were placed at 0.3–0.5 mm intervalsmediolaterally and rostrocaudally. Penetrations across area 3b were placedapproximately 1 mm apart mediolaterally. The location of pre- and post-injection penetrations were the same. Microelectrodes were hydraulical-ly advanced through cortex and thalamus until single- or multiple-unitresponses to mechanical stimulation of the body could be isolated. Smallmarker lesions (10 µA for 10 s) were placed in the thalamus and cortex atstrategic points to assist in locating the recordings sites post mortem.

HISTOLOGICAL ANALYSIS. On completion of all electrophysiologicalrecording experiments, animals were given a lethal dose of pentobar-bital and then perfused intracardially with 0.9% saline followed by 4%paraformaldehyde. Brains were cut in the coronal plane on a freezingmicrotome into 50 µm sections, and every fifth section was mountedand stained for Nissl substance to assess the placement of recordingtracks, marker lesions, and placement of the cannulae in cortex.Recording sites were identified by reconstructing electrode tracks andmarker lesions as described25.

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seem to further eliminate retrograde degeneration as a possiblemechanism explaining our results.

Although some earlier electrophysiological studies of the nor-mal thalamus in monkeys have reported ‘extra-lemniscal’ neu-rons with large RFs11,12, such RFs were localized almostexclusively in the VPLo (oralis) nucleus11, far anterior to the VPLc(caudalis)14 where our recordings were made. In addition, record-ings lateral and medial to the affected thalamic zone indicatedneurons had normal RF size, further corroborating that we wererecording within VPLc, and not in the extralemniscal pathway.Finally, histological analysis from our cases confirmed that ourrecordings were from the hand region in VPLc. Importantly, therewas no evidence of any degeneration of neurons in the thalamusor cortex. Regardless of the precise mechanism(s) responsible forthe expansion, however, the magnitude of the RF expansion iscompletely unexpected and highlights the contribution of feed-back processing loops on RF properties.

Many previous studies of adult neural plasticity after periph-eral perturbations have focused attention on the earliest point inthe ascending pathway where plastic changes could occur (spinalcord15,16, brainstem17,18, or thalamus19–21), with the interpreta-tion that plastic changes at early stations are simply relayed tocortex. The timing, nature and magnitude of our present find-ings challenge this view of the system as a simple hierarchicalpathway22,23, providing a definitive demonstration of a dramat-ic and substantial role for the cortex on neuronal processing earlyin the somatosensory pathway. This study demonstrates thatsome RF characteristics within somatosensory pathways resultfrom a series of interconnected dynamic loops, with changes atany given level capable of triggering extensive changes in the RFsof neurons at both earlier and later stations in the processingchain. Such a view of feedback connections is entirely consistentwith a recent hypothesis24 that recognizes a substantial role forcorticothalamic feedback loops on the modification of receptiveproperties but not for the major driving of thalamic neurons bythe cortex. The extent to which such feedback connections mod-ulate activity and the precise mechanisms responsible for suchmodulation should be ripe areas for future research.

MethodsSURGICAL PROCEDURES. All procedures in the present study were approvedby the Wake Forest University Animal Care and Use Committee. All mon-keys used in this study were Macaca mulatta. Monkeys were anesthetized

Fig. 3. RF size in VPL before and after acute cortical D-APV administration. (a) Distribution histogram ofRF sizes for recording sites localized within the VPL hand representation before (pre) and after (post)acute cortical D-APV administration. RFs were categorized as in Fig. 2. (b) Representative RFs recordedfrom sites localized within VPL before (pre) and after (post) acute cortical D-APV administration.

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DATA ANALYSIS. Percent responsive sites was determined as the number ofresponsive sites per total number of sites. Percent large RF sites are givenas number of sites with RFs encompassing one or more digits (includ-ing RFs encompassing the hand and forearm) per number of hand-responsive sites. In the chronic D-APV animals the infusion zone wasdefined as the region of cortex surrounding the cannula site in whichresponsiveness was largely suppressed (90% of recording sites) and cor-responded to a 5 mm mediolateral expanse of cortex within the handrepresentation. The fringe zone was defined as the region in whichresponsiveness was only partially suppressed (25% of sites) and extend-ed approximately 1 mm medial and lateral to the infusion zone. Corti-cal recordings indicated that the face representation was not affected bythe D-APV administration.

AcknowledgementsThis research was supported by NIH grants MH11950-01, MH53369-02 and

NS35246-01.

RECEIVED 20 MAY: ACCEPTED 26 MAY 1998

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