# Cortical map remodeling in the intact hemisphere and functional recovery after focal lesion to the primary somatosensory cortex

Justine Facchini, Christian Xerri, Abdessadek El Ahmadi, Isabelle Watabe, Nicolas Catz, Yoh'I Zennou-Azogui

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Justine Facchini, Christian Xerri, Abdessadek El Ahmadi, Isabelle Watabe, Nicolas Catz, et al. Cortical map remodeling in the intact hemisphere and functional recovery after focal lesion to the primary somatosensory cortex. Neurobiology of Disease, 2025, 214, 10.1016/j.nbd.2025.107043. hal-05290619

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# Cortical map remodeling in the intact hemisphere and functional recovery after focal lesion to the primary somatosensory cortex

Justine Facchini, Christian Xerri, Abdessadek El Ahmadi, Isabelle Watabe, Nicolas Catz, Yoh'i Zennou-Azogui*

Aix-Marseille University - CNRS, Center for Research in Psychology and Neuroscience (CRPN), UMR 7077, Marseille, France

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## ARTICLE INFO

**Keywords:**

Focal cortical lesion

Electrophysiological cortical mapping

Contralesional somatosensory cortex

Cutaneous forepaw representation

Fine postural adjustments

Hemispheric interactions

## ABSTRACT

After injury to the primary somatosensory cortex (S1), most studies have focused on perilesional remodeling and its role in functional recovery. In contrast, alterations within the contralesional cortex remain poorly understood, even though the interhemispheric communication is disrupted by the lesion. Using electrophysiological mapping, we investigated in rats the time-course of cutaneous map remodeling in the intact hemisphere following uni- lateral focal damage to the forepaw area in S1 along with behavioral assessment of sensorimotor deficits. Cortical maps showed a representational dedifferentiation inducing a degradation of the somatotopic organization, starting immediately after the lesion and worsening until the end of the 14th day post-injury. These changes were underpinned by a dramatic enlargement of cutaneous receptive fields accompanied by an increase in neuronal sensitivity. Strong impairment of tactile sensitivity and sensorimotor adjustments was shown for the forepaw contralateral to the injured hemisphere, that gradually abated from the 2nd to the 7th week. Interestingly, deficits of fine sensorimotor adjustments were also observed in the "non-paretic" forepaw. They were less pro- nounced than in the "paretic" limb but evolved with a similar time course of recovery. A substantial restoration of somatotopic organization occurred gradually, in parallel with the functional recovery. Immediate post-lesion effects suggest an altered interhemispheric interplay and highlight the critical role of hemispheric cross in- fluences in maintaining fine somatotopic organization of cutaneous maps in each hemisphere. S1 map normal- ization in intact cortex paralleling functional recovery may reflect compensatory mechanisms reorganizing interhemispheric communication and shaping cortical neurons' responses.

## 1. Introduction

Brain injuries, including traumatic brain injuries and stroke, are among the leading causes of long-term sensorimotor disabilities. Nonetheless, a substantial recovery is observed during the weeks and months following stroke. Numerous investigations in both humans and animals have extensively described the anatomical and functional changes occurring in the injured hemisphere, particularly within per- ilesional areas, in an attempt to elucidate their potential contribution to the functional restoration (for reviews: Alia et al., 2017; Caleo, 2015; Xerri et al., 2014). Yet, despite the wealth of data on post-lesion re- covery, the underlying neurophysiological mechanisms remain poorly understood.

Electrophysiological mapping studies have shown that neural sub- strates of manual skill recovery reside in the remodeling of functional representations within the peri-lesion sectors of the motor (M1) (Nudo

et al., 1996) or somatosensory (S1) cortex areas (Jenkins and Merzenich, 1987; Xerri and Zennou-Azogui, 2003). In addition, remodeling of the somatotopic organization occurs within areas of S1 (1 and 3a) after an infarct in 3b (Xerri et al., 1998) or within the ventral premotor cortex after a focal infarct in M1 (Dancause et al., 2005). Interestingly, these cortical changes were found to develop in parallel with the recovery of fine manual skills. Specifically, the sequence and kinetics of the reac- tivation of peri-lesion cortical regions have been investigated using *in vivo* 2-photon calcium imaging (Winship and Murphy, 2009) and voltage-sensitive dye imaging (Brown et al., 2009). These studies showed a gradual remapping of the damaged representation in the hindlimb somatosensory and motor areas, after a focal cortical lesion targeting the forepaw area in S1.

However, post-lesion compensatory reorganization is not confined to the perilesion or remote areas of the injured hemisphere, as it also occurs in various distant regions of the contralesional hemisphere sharing

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: yohi.zennou-azogui@univ-amu.fr (Y. Zennou-Azogui).</footnote>
anatomo-functional connections with the damaged cortical area (Xerri et al., 2014). Unilateral cortical injury leads to a disruption of inter-hemispheric balance, leading to a temporary or enduring increased activation of the contralesional cortex that is related to a release of inhibition from the injured hemisphere, as shown in neuroimaging studies in humans (Rossini et al., 2007; Tang et al., 2015) and rodents (Mohajerani et al., 2011). This disruption accounts for the severity of functional deficits (Murase et al., 2004). The available evidence suggests that after a transitory period of recruitment of motor-related areas in the contralesional cortex, there is a refocusing of motor activation in the ipsilesional cortex. This activation, which partially reflects a restoration of the interhemispheric balance, is correlated with a more complete recovery of hand skills (Rehme et al., 2011; Ward et al., 2003). However, whether the recruitment of the contralesional areas has an adaptive or detrimental effect on the recovery remains under debate (Casula et al., 2021; Dancause et al., 2015; Dodd et al., 2017; Xerri et al., 2014).

It is noteworthy that the vast majority of studies on sensorimotor dysfunction following brain injury focused on motor disorders and/or related changes in motor cortical areas. By contrast, somatosensory dysfunction has been less studied, despite the fact that 50 % of stroke patients suffer from sensory discrimination impairment in the parietal hand (Carey and Matyas, 2011; Connell et al., 2008). In addition, most of the cortical neuron studies after injury in the somatosensory cortex targeted the perilesional regions, whereas only a few studies investigated contralesional effects (Merino-Serrais et al., 2023; Mohajerani et al., 2011; Reinecke et al., 2003; Rema and Ebner, 2003; Sakatani et al., 1990). Furthermore, evidence from human (Blankenburg et al., 2008; Brodie et al., 2014; Hlushchuk and Hari, 2006) and animal studies (Catania and Kaas, 2001; DeCosta-Fortune et al., 2020; Jones et al., 1979; Shin et al., 1997) indicates that, similarly to the motor system, interhemispheric interplay occurs between homologous somatosensory areas. Nevertheless, it is not yet clear how changes in neuronal activation of the somatosensory areas in the contralesional hemisphere impact the functional recovery. Moreover, the spatial and temporal pattern of these cortical changes remain to be characterized.

Thus, the main objective of the present study was to analyze the time-course of neurophysiological changes affecting the contralesional somatosensory cortex, in parallel with the evolution of behavioral deficits during the functional recovery process, in a rodent model of focal injury to S1. To achieve this aim, we performed cortical electrophysiological mapping of the forepaw cutaneous representation in S1, combined with behavioral assessment of postural adjustments and tactile sensitivity, at various time-points following the lesion.

# 2. Methods

## 2.1. Animals and experimental protocols

In this study, 43 male Long-Evans rats weighing 300 ± 30 g were used. All experiments were performed in accordance with the directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. The present study was approved by Neurosciences Ethics Committee N°71 of the French National Committee of animal experimentation. Each step of these experiments, from conception to implementation, was carried out under the supervision of a veterinarian and in agreement with the National Ethics Committee. Every attempt was made to respect the 3Rs rule in order to minimize both the number and the suffering of the animals used in this experiment. Animals were housed under standard laboratory environmental conditions in groups of three in plexiglass cages (26.5 cm wide × 42.5 cm deep × 18 cm high). Food and water were provided *ad libitum*.

We performed electrophysiological cortical mapping of the contralesional cutaneous forepaw representation in S1 cortex in intact rats (CTRL, *n* = 7), in the first hours following the lesion (D0, *n* = 6), and at other time points, between 7 and 50 days post-injury, in different groups

of rats (D7, *n* = 6; D14, *n* = 6; D21, *n* = 6; D28, *n* = 7; D50, *n* = 3) (Fig. 1). The challenges inherent in longitudinal post-injury studies, such as animal survival and the occurrence of unexpected infections, led us to prioritize cortical mapping during the first post-injury month. As a result, only three rats were used at D50. At the completion of mapping, the animals' brains were perfused and collected for histological evaluation of lesion size.

In parallel with the cortical mapping, the animals underwent behavioral tests to evaluate their functional deficits and the kinetics of recovery. Behavioral assessment was performed twice, two days apart, before the lesion and then every two days after lesion induction until the day of cortical mapping. For this purpose, we performed three behavioral tests assessing the sensorimotor abilities of the animals: the inclined ladder test, the cylinder test, and the adhesive removal test. Pre-lesion and post-lesion behavioral data were collected in the same animals until the day of cortical mapping on D28 (ladder test: *n* = 8; cylinder test: *n* = 9; adhesive removal test: *n* = 6) and D50 rats (*n* = 3 for the 3 tests).

## 2.2. Surgical procedures

### 2.2.1. Induction of focal cortical lesion

Animals were anesthetized with intraperitoneal injection of ketamine 1000 (25 mg/kg, Virbac, France) and medetomidine (0.25 mg/kg, Domitor® OrionPharma, Finland). Anesthesia was maintained throughout the procedure by injection of a half dose of this mixture administered every hour. A local anesthetic (Xylocaine, Xylovet®) was applied to the scalp and external auditory meatus to minimize the pain generated by the ear bars. The head was held in a stereotaxic frame at the level of the incisors and the ear bars. Body temperature was continuously monitored by a rectal thermo probe and maintained between 37.5 °C and 38 °C by a homeothermic feedback blanket (Harvard Apparatus Ltd., Kent, UK). The animal was hydrated by a subcutaneous injection (2.5 ml) of a mixture of equal parts NaCl and glucose (5 %). During the lesion, repeated injections of a cocktail of saline and glucose were given every 2 h to maintain the animal in a stable physiological state. The surgery and lesioning procedures were performed under aseptic conditions. Antibiotic prophylaxis (ceftazidime, Fortum®; 15 mg/kg) was used before the beginning and at the end of the surgery, and repeated the day after, to prevent infection.

To prevent cerebral edema, an incision was made between the first vertebra and the skull, and after the posterior neck muscles were removed, the cerebrospinal fluid was drained through an opening in the dura mater overlying the *foramen magnum*. The scalp was then incised, and after detaching the connective tissue and lateral muscles overlying the parietal bone, a craniotomy (about 5 × 5 mm) was performed with the bregma as a reference point (posterior: 1–5 mm; lateral: 2–6 mm) to expose the forepaw area of S1. The removed bone flap was kept hydrated in NaCl so that it could be placed back at the end of the procedure. After incising and resecting the dura mater, the surface of the exposed parietal cortex was bathed in NaCl to prevent drying and cortical edema.

First, a quick electrophysiological assessment was made to determine the global limits of the forepaw representation in S1 (see below). Then, a temperature-controlled electrode (Radionics TCZ, Kopf, USA) was moved with a micromanipulator over the cortex and slowly positioned in contact with the cortical surface. A radiofrequency current (500 MHz) was delivered through the electrode placed on the cortex so that the temperature was progressively increased at its tip, until it reached 80 °C for 1 min. This temperature was then maintained for 3 min. In addition to the direct destruction of the brain tissue, the heat generated in the cortex induced focal lesion characterized by occlusion of the vessels, leading to blanching of the area around the probe tip (Fig. 1B). Care was taken to preserve major arteries and veins, while occluding their local branches over the forepaw cortical area, ensuring that the lesion remains spatially confined to the targeted area. Several lesion points (4 to 5) were performed in S1 to damage the entire forepaw representation in S1,
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<figure><img src="image_13.png" /><figcaption>**Fig. 1.** Experimental protocol for evaluating remodeling of forepaw cutaneous cortical maps after focal injury. **A:** We performed electrophysiological cortical mapping of the forepaw contralesional cutaneous representation in S1 cortex in the first post-injury hours and at different time points over the subsequent weeks. Behavioral assessment was performed every 2 days after the injury to assess rat's behavioral deficits and recovery (sample sizes are indicated) **B:** Lesion procedure: radiofrequency-induced hyperthermia was performed using a temperature-monitoring electrode (500 MHz radiofrequency current). Temperature was raised to 80 °C within one minute and maintained at this level for 3 min. The heat generated in the brain tissue induced a focal infarct characterized by a visible vessel occlusion leading to a neuronal death within the targeted forepaw area. The zone of vessel occlusion is outlined on the mapped cortical area prior to and immediately after the lesion (continuous and broken lines, respectively); the brain slice image stained with Nissl shows a typical cortical injury **C:** Schematic illustration of the cortical mapping procedure. In each group, cortical recordings (about 70 sites per map; C1) were performed in layer IV in the contralesional forepaw representational zone of S1 to determine the location and size of the neurons' cutaneous receptive fields (RFs). The nomenclature indicates RF location on the forepaw skin surface (C2). An example of a RF recorded in the mixed cortical area is represented by a red circle encompassing parts of digits 3 and 4, and pad 2. Collection of all RFs recorded in a mapping session (C3) in order to generate a somatotopic cortical map (C4) **D:** Behavioral tests used to evaluate functional deficits and recovery after injury to S1 forepaw area. Ladder-walking test (left): this test was used to quantify skilled forepaw placement on the ladder rungs during locomotion. A neurological score was computed for each forepaw during upward and downward displacements on the ladder. Cylinder test (middle): this postural test evaluated the asymmetry of forepaw contacts with the cylinder wall for postural support during rearing. Adhesive removal test (right): tactile sensitivity deficits were assessed by applying a piece of adhesive tape (1 × 1 cm) on the palm of each forepaw. The time required for the animal to detect and remove the tape was counted. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</figcaption></figure>

which was verified thereafter by electrophysiological recordings in a few cortical sites.

This model of focal injury has been used previously in our laboratory in studies of acute and chronic cortical map plasticity after focal cortical

lesion (Coq and Xerri, 1999a; Xerri and Zennou-Azogui, 2003, 2014). It produces highly localized and reproducible brain lesions. Precise control of lesion temperature and duration ensures consistent lesion sizes, which is critical for comparing neurophysiological and behavioral outcomes
across experimental groups. This procedure induces a secondary, not primary, ischemic lesion, in the sense that it is not vascular in origin. However, it selectively disrupts blood flow through small vessels, thus leading to localized ischemia within the lesion core. Radiofrequency-induced hyperthermia produces cellular injury, i.e., coagulation necrosis, neuronal shrinkage, nuclear pyknosis and perineuronal astrocytic swelling (Ohmoto et al., 1996) which is associated with cerebral ischemia. Moreover, localized hyperthermia induces increased extracellular glutamate concentrations that reaches neurotoxic levels (Adachi et al., 1995). Interestingly, reperfusion typical of focal ischemic injury is often observed within the lesion perimeter.

In the D0 rats, the contralesional S1 was then exposed using the procedure described above, and the forepaw cortical mapping was systematically performed. In the other injured rats, which were allowed to survive for behavioral assessment and future remapping, a local anti-biotic (Flumiquil®, Ceva Santé Animale) was applied to the lesioned cortex which was then covered with a piece of Teflon® membrane. The bone flap was replaced, then stabilized and sealed with dental cement before the neck muscles and scalp were sewn back. A non-steroidal anti-inflammatory analgesic was administered before the animal woke up (Tolfedine, Vétiquinol, 4 mg/kg, i.m.). The injured rat was then placed in a post-operative room under increased surveillance for the duration of its recovery. It was kept alone in a cage with jelly food and water *ad libitum* for two days and then housed with two congeners.

### 2.2.2. Cortical electrophysiological mapping

#### 2.2.2.1. Surgical procedure.
Cortical mapping was performed in the S1 of the contralesional hemisphere, in the area of cutaneous representation of the forepaw (Fig. 1C). Conventional multi-unit monitoring and receptive field mapping techniques were used to reconstruct the forepaw representation in layer IV of S1. The mapping procedure used in the present study has been described in detail in previous papers (Xerri et al., 1999; Zennou-Azogui et al., 2016). We used a high-resolution camera mounted on an operating microscope to obtain magnified images of the cortical area to be mapped and the contralateral ventral and dorsal surfaces of the forepaw. A magnified image of the exposed cortex was used to guide and record the location of electrode penetrations relative to the vascularization of the cortical surface. During mapping, a thin layer of warm silicone fluid was applied to the cortical surface to prevent drying. Electrophysiological assessment was conducted by using parylene-coated tungsten microelectrodes (approximately 1 MΩ at 1 kHz; WPI, UK) inserted perpendicular to the cortical surface and moved in coordinates using a three-dimensional (x, y, z) micromanipulator driven by stepper motors (Märzhauser, FST; Germany). Electrode penetration sites were identified in relation to the vascularization of the cortical surface. For all rats, the interelectrode penetration distance was between 50 and 100 µm. The multi-unit signal was pre-amplified, filtered (bandwidth: 0.5–5 kHz) and displayed on an oscilloscope. This signal was also rectified and passed through a discriminator whose output was proportional to the portion of the input signal that was above an adjustable threshold set just above the background noise. The output of the discriminator was then passed to an audio monitor. Using the artifact generated by the contact of the microelectrode with the surface of the cortex as a zero level, we advanced the electrode to a depth of approximately 650–700 µm to record the responses of small groups of neurons in layer IV (Waters et al., 1995; Welker et al., 1984). Under our electrophysiological conditions, the background noise amplitude was generally between 15 and 20 µV with a signal-to-noise ratio between 4 and 6.

At each site, the evoked cortical responses, detected as large bursts of activity, allowed us to classify the neuronal responses as cutaneous or non-cutaneous. Cutaneous receptive fields (RFs) were defined as the area of the skin where a barely visible indentation of the skin or deflection of the hair caused reliable changes in multi-unit activity. This

skin stimulation was produced with a fine-tipped wooden stick and monitored with magnifying glasses (x4). Non-cutaneous responses were identified by tapping and pressing on tendons, intrinsic muscle, or joint manipulations, where no cutaneous responses were found. Cortical sites showing only spontaneous discharges were classified as non-responsive. Ridges on the hairless skin of the fingers and the palm were used as reliable landmarks to delineate RFs which were drawn on an image of the ventral or dorsal forepaw.

The mechanical threshold of neural responses to skin stimulation recorded in cortical areas of glabrous skin was determined using Von Frey monofilaments (Semmes-Weinstein Aesthesiometer, Stoelting, Wood Dale, IL) that apply indentation stimuli at a relatively constant predetermined force. The most commonly used filaments were 2.36 (bending force: 0.02 g; bending pressure: 4.39 g/mm²), 2.44 (0.04 g; 4.93 g/mm²), 2.83 (0.068 g; 5.37 g/mm²), 3.22 (0.166 g; 9.15 g/mm²), 3.61 (0.407 g; 16.36 g/mm²) and 3.84 (0.692 g; 21.39 g/mm²). We used a series of stimuli of increasing and decreasing forces to determine the mechanical threshold causing noticeable changes in neuronal discharge. Stimulation consisted of gently pressing a filament against the ventral skin, perpendicular to its surface and in the center of the RF, until the filament began to bend. This procedure was performed 5 to 10 times for each filament. The mechanical threshold is conventionally used as a measure of the sensitivity of the neuronal response.

#### 2.2.2.2. Experimental measurements.
After the mapping session, the individual sizes of the different receptive fields recorded were measured offline using a custom application created with MATLAB (The Mathworks, Inc.). Glabrous and hairy skin RFs were measured in mm² and normalized to the total skin area (ventral + dorsal) of the forepaw measured on the scanned images. The average relative size of all recorded RFs was calculated for each experimental group. We distinguished three categories of RFs: *ventral* (located on the glabrous part of the paw), *dorsal* (located on the hairy part) and *ventro-dorsal* RFs. The relativized sizes of each category of RFs were then averaged for each experimental group. The mechanical thresholds of neuronal responses to stimulation of the forepaw ventral skin (i.e., of *ventral* and *ventro-dorsal* RFs) obtained using the Von Frey filaments were processed to calculate an average pressure threshold (weighted mean in g/mm²) for each group.

The Canvas X Draw software (Canvas GFX) was used to reconstruct the cutaneous map of the forepaw representation in each rat, based on the location and size of the RFs. Boundaries encompassing cortical sites whose RFs were restricted to a common forepaw subdivision (e.g., finger, palm pad, etc.) were drawn. Thus, nearby cortical sites responding to stimulation of the same skin area were grouped in the same cortical territory of the map. The boundary between two territories was drawn halfway between two adjacent points for which the RFs were restricted to 2 distinct parts of the paw. The boundary crossed the recording site when it corresponded to a single RF that overlapped distinct but adjacent parts of the skin (e.g., a RF including fingers 3 and 4). The map distinguishes simple areas corresponding to the representation of a restricted area of the paw, such as a finger or a palm pad, as well as those activated by nail movement. These simple areas are ventral (i.e. representing glabrous skin surfaces) or dorsal (i.e. representing hairy surfaces). *Ventro-dorsal* sectors of the map include cortical sites displaying RFs on both ventral and dorsal skin surfaces. When RFs were located on two or more skin subdivisions of the forepaw (e.g. 2 or 3 fingers), we grouped the cortical sites into so-called *mixed* areas. Cortical zones defined as *paw* comprise sites in which RFs included the entire ventral or dorsal surface of the forepaw (Fig. 1C). The Canvas X Draw software computes the surface area (in mm²) of each of the different cortical sectors, which was then expressed in % (± SEM) of the total surface of the cutaneous map.

The mechanical thresholds obtained using the Von Frey filaments were processed to calculate an average pressure threshold for each
animal. Every threshold value (4.39, 4.93, 5.37, 9.15, 16.36 and 21.39 g/mm²) was multiplied by the number of recording sites displaying that threshold, and the sum of these weighted values was divided by the total number of sites tested in each animal. A mean threshold was then calculated for each experimental group.

## 2.3. Behavioral assessment

**Inclined ladder test** - Sensorimotor functions were assessed by placing the rat on a 1 m long ladder inclined at 45°, on which the animal had to make 3 round trips (**Fig. 1D, left**). This locomotor test allows us to evaluate the sensorimotor deficits of the forepaws. A mirror was placed under the ladder so as to visualize and video the movement of the forepaw. The rungs were placed at equal distances from each other. A quantitative assessment of paw placement errors was performed by analyzing of off-line video recordings in slowed playback. A score from 0 to 2 was assigned to the different paw placements (2: correct paw placement, 1: the animal misplaces its paw on a bar, or the paw passes through the bars to the wrist; 0: the paw passes through the bars to the elbow or shoulder (Martinez et al., 2011)7/28/2025 7:43:00 AM. At each post-lesion day, a mean score was calculated for each forepaw for the 3 ascents and 3 descents performed by the animal on the ladder.

**Cylinder test** - The postural asymmetry of the animals was tested by placing them in a transparent cylinder (Ø: 20 cm, height: 30 cm) (**Fig. 1D, middle**). The spontaneous behavior of the animals was filmed over a period of 10 min. This postural test evaluates the asymmetry of postural supports with the forelimbs when the animal is standing upright and thus quantifies the relative use of each forelimb. The videos were then analyzed off-line to count the number of times each forelimb was used to make the first touch onto the wall of the cylinder during vertical rearing. An asymmetry index (AI) was calculated by comparing the scores for each forelimb: AI = [average score (paretic) - average (non-paretic)] / [average score (paretic) + average (non-paretic)]. An AI <0 indicated a preferential use of the non-paretic forepaw.

**Adhesive removal test** - Tactile sensitivity was assessed by applying a piece of tape (1 × 1 cm) to the palm of each of the animal's forepaws (**Fig. 1D, right**). The tape was applied three times to the non-paretic paw and to the paretic paw in a random fashion. The time required for the animal to detect and remove the tape was counted. Mean detection times were then calculated for the paretic and the non-paretic forepaw. This test provides indication about tactile deficits of the forepaws.

## 2.4. Histological procedure for lesion size evaluation

Rats were deeply anesthetized with a mixture of ketamine/medetomidine and then perfused by intracardiac injection of 400 ml of isotonic saline (0.9 % NaCl) followed by 400 ml of freshly prepared solution (4 % paraformaldehyde in 0.1 M phosphate buffer, pH: 7.4). Then, the brains were carefully dissected out and post-fixed for 12 h at 4 °C in a 4 % paraformaldehyde solution containing 10 % sucrose in phosphate buffer. The brains were cryoprotected by successive transfers into increasing concentrations (10 %, 20 % and 30 %) of sucrose solution in 0.1 M phosphate buffer saline (PBS) for 72 h at 4 °C. For histological examination, the brains were frozen with carbon dioxide and 40-μm-thick coronal sections centered on the cortical lesions were performed using a cryostat. Histological sections were mounted on slides (four per slide) and one out of every three slides was Nissl stained with cresyl violet in order to assess morphological alterations occurring within the lesioned zone. Sections were digitally imaged, and the area of the lesion was manually outlined and measured on each section. Stereological estimation of lesion size was performed, and a mean lesion volume was calculated for each experimental group (D7, D14, D21, D28 and D50).

## 2.5. Statistics

The variables collected in this study display a variety of distribution

patterns. Some are strictly positive and follow a Gamma distribution (e. g., RF size or detection time in the adhesive removal test), others are discrete and conform to a Binomial distribution (e.g., cortical map areas) or a Poisson distribution (e.g., ladder test score), while still others adhere to a Gaussian (normal) distribution (e.g., asymmetry index in the cylinder test). Notably, all these distributions can be regarded as specific instances within a more comprehensive and well-established framework: the exponential family of distributions (Efron, 2022). This diversity in distribution patterns motivated the use of statistical models capable of handling such heterogeneity, leading us to adopt generalized linear models (GzLMs) (Dunteman and Ho, 2005; Gill and Torres, 2020). As in ANOVA or regression analyses, the purpose of GzLMs is to relate response variables to linear combinations of predictor variables. For categorical explanatory variables, we implemented a binary encoding scheme, converting them into dummy variables. In this process, we designated the control group as the reference category. We used an identity link between the dependent variable and the systematic part of the GzLM. This enables us to interpret the model estimated parameters ($b_i$) as contrasts ($m_i$ – $m_c$) between means of the control group ($m_c$) and the experimental groups ($m_i$), thereby facilitating meaningful comparisons.

Statistical analyses were carried out using JASP (Version 0.19.3, 2025), Jamovi (Version 2.5, The Jamovi Project, 2024), and R (Version 4.2.2, R Core Team, 2024). These software packages offer user-friendly interfaces and advanced statistical capabilities, allowing researchers to apply generalized linear models (GzLMs) with ease and flexibility.

Within the framework of GzLMs, we primarily relied on the likelihood ratio test (LRT) to compare nested models and assess the significance of main effects and interactions in our electrophysiological data. To further enhance interpretability and ensure robust comparisons, the LRTs were transformed into deviances and subsequently into Fisher statistics, accounting for their respective degrees of freedom (df). Additionally, for more granular comparisons, we applied Wald tests [$z_i = b_i/SE(b_i)$] to evaluate specific contrasts between means of the control group ($m_c$) and the experimental groups ($m_i$). These tests provide pointwise evaluations of individual parameter estimates, complementing the broader assessments afforded by the LRT.

The same statistical methods, including likelihood ratio tests and Fisher transformations of deviances, were applied to the behavioral data, with appropriate adjustments made to account for the repeated measures design and potential within-subject correlations.

This combination of statistical methods—employing both global assessments via LRT and localized evaluations through Wald tests—ensures a comprehensive understanding of the data, allowing us to draw robust conclusions about the effects under investigation. All reported F-statistics and their associated degrees of freedom are included throughout the manuscript to provide transparency and facilitate reproducibility. Mean (± SEM) values are used throughout the manuscript. Median values (± IQR) are also shown in figures.

# 3. Results

## 3.1. Remodeling of cutaneous RFs

The cutaneous representations of the forepaw were reconstructed on the basis of about 70 sites per mapping session. We recorded a total of 1632 cutaneous RFs in 41 rats belonging to intact and lesioned groups of rats recorded at different post-lesion times.

We found that the spatial extent of the cutaneous RFs was altered during the post-lesion period examined [F (6, 1625) = 142.25, *p* < 0.0001] (**Fig. 2B**). A significant increase in the mean RF size was recorded from the first hours post-lesion (CTRL: 3.29 ± 0.14 %; D0: 11.50 ± 0.58 %, *p* < 0.0001) until D14 (D7: 14.53 ± 0.90 %, *p* < 0.0001; D14: 17.79 ± 1.48 %, *p* < 0.0001). After D14, the mean RF size was found to decrease gradually, but remained significantly greater than the CTRL value until the end of the post-lesion period examined (D21: 8.65
<figure><img src="image_14.png" /><figcaption>**Fig. 2.** Impact of contralateral cortical injury on the size of forepaw cutaneous receptive fields (RFs) of S1 neurons. **A:** Typical RFs located on the forepaw glabrous (top) and hairy (bottom) skin surfaces of an intact rat (CTRL), and lesioned rats at different time points post-injury. **B:** Mean relative size of all RFs obtained in CTRL and injured rats. Boxplots represent the first and the third quartiles and medians, while grey dots show individual values. **C-D-E:** Mean relative size of *ventral*, *dorsal* and *ventro-dorsal* skin RFs taken from the data shown in **B**. Statistical differences between the experimental groups and the CTRL group are indicated. \*: p < 0.01; \*: p < 0.001; \*: p < 0.0001.</figcaption></figure>

± 0.52 %, p < 0.0001; D28: 6.63 ± 0.32 %, p < 0.0001; D50: 4.21 ± 0.22, p = 0.018, note that D50 S1 mapping was only performed in 3 animals).

We observed an important variability in the distribution of RF sizes within each group. Thus, to gain further insight into the cortical impact of the cortical injury, we distinguished the *ventral* from the *dorsal* and the *ventro-dorsal* RFs for each group. First, considering the changes in ventral skin RFs, we found the same temporal profile as that reported for the whole RF population [F (6, 1154) = 135.6, p < 0.0001]. Compared to the intact rats, the *ventral* RF size increase reached a maximum value from the 7th to the 14th post-lesion day (CTRL: 2.80 ± 0.09 %; D0: 9.54 ± 0.54 %, p < 0.0001; D7: 11.36 ± 0.72 %, p < 0.0001; D14: 11.18 ± 1.06 %, p < 0.0001) (Fig. 2C). Then, from the 21st post-lesion day, the *ventral* RF diminished progressively until the 50th post-lesion day where the mean size approached the CTRL value, but remained significantly larger (D21: 7.22 ± 0.46 %, p < 0.0001; D28: 5.49 ± 0.25 %, p < 0.0001; D50: 4.31 ± 0.23, p < 0.0001).

Considering the dorsal skin RFs, we found a significant size increase

after the first hours post-lesion until the first two weeks; then, they diminished gradually and became even smaller than prior to the lesion at the 50th post-lesion day [F (6, 195) = 32.5, p < 0.0001; CTRL: 4.53 ± 0.39 %; D0: 8.98 ± 2.13 %, p = 0.157; D7: 24.92 ± 7.55 %, p < 0.002; D14: 23.77 ± 7.74 %, p < 0.001; D21: 8.26 ± 2.21 %, p < 0.0001; D28: 8.59 ± 1.49 %, p < 0.0001; D50: 2.93 ± 0.36, p < 0.0001] (Fig. 2D). Interestingly, we found less numerous *dorsal* RFs after the injury, than in the control. This difference cannot be ascribed to a bias in the mapping procedure, as the spatial resolution of mapping was similar across all sessions. We hypothesized that the *dorsal* RF enlargement could lead to the occurrence of RF extending on both ventral and dorsal skin.

None of these *ventro-dorsal* RFs was found in the CTRL group, but they were observed from the first post-injury hours until the 50th day. Indeed, the proportion of “extra-large” RFs progressively increased until D14 and then gradually diminished (D0: 24 %, D7: 30 %, D14: 40 %, D21: 17 %, D28: 10 %, D50: 1 %). When comparing the size of these *ventro-dorsal* RFs recorded after the lesion, we found a significant global effect between post-lesion groups [F (5, 262) = 4.65, p < 0.001]. These
RFs were expanded as early as D0 (D0: 17.60 ± 1.50; one-sample Wald z-test, *p* < 0.001). The RF size was then similar among post-lesion groups, except in D14 rats in which they were even larger than at D0 (D7: 19.43 ± 1.91 %, *p* = 0.469; D14: 24.12 ± 2.52 %, *p* = 0.021, D21: 15.37 ± 1.67 %, *p* = 0.417; D28: 14.15 ± 1.28 %, *p* = 0.208) (Fig. 2E). Fifty days after the lesion, only one *ventro-dorsal* RF (size: 7.96 %) was found among the whole RF populations recorded in 3 rats.

It is very likely that the RF expansion was due to a substantial increase in neuronal excitability. Hence, we assessed the mechanical threshold of the neuronal responses reflecting their sensitivity to a light pressure exerted on the skin. From the first hours and until the 28th post-lesion day, the neuronal sensitivity in the cortical area representing the contralesional forepaw was greater than in the CTRL group [F (6, 32) = 6.30, *p* < 0.001], as attested by smaller thresholds of response to the mechanical stimulation of ventral skin surfaces. The strong decrease in neuronal sensitivity recorded at D0 was maintained during the first two post-lesion weeks with a gradual return to control values at the 50th day (CTRL: 15.61 ± 0.65 g/mm²; D0: 8.39 ± 1.52 g/mm², *p* < 0.0001; D7: 8.51 ± 0.86 g/mm², *p* < 0.0001; D14: 6.98 ± 0.60 g/mm², *p* < 0.0001; D21: 10.70 ± 1.73 g/mm², *p* < 0.01; D28: 12.10 ± 1.32 g/mm², *p* < 0.05; D50: 14.93 ± 1.21 g/mm², *p* = 0.751) (Fig. 3).

## 3.2. Spatial organization of somatosensory maps

The somatotopic organization of the forepaw representation within the contralesional S1 cortex displayed invariant organizational features, despite inter-individual differences in representational details. The cutaneous representation was somatotopically organized with clearly segregated individual digits and palm, qualified as *simple* areas, ordered from the anterolateral to posteromedial cortical sectors (Fig. 4A). Additionally, after the lesion, the cortical maps showed *mixed* representational areas corresponding to neurons whose RF spread over two or more normally differentiated skin territories of the forepaw; also, we found few neurons with RFs extending over the whole ventral or dorsal side of the forepaw, thus defining a *paw* area in the cutaneous map.

After the lesion, the overall map size was not significantly modified throughout the post-lesion period examined [F (6, 34) = 0.603, *p* = 0.726; CTRL: 2.07 ± 0.18 mm²; D0: 1.72 ± 0.41 mm²; D7: 1.46 ± 0.33 mm²; D14: 1.77 ± 0.33 mm²; D21: 1.99 ± 0.35 mm²; 8: 1.66 ± 0.13 mm²; D50: 1.45 ± 0.05 mm²] (Fig. 4B). However, the post-lesion increase in RF size described above led to changes in the spatial configuration of the somatotopic maps.

<figure><img src="image_15.png" /><figcaption>**Fig. 3.** Neuronal responsiveness to stimulation of the forepaw ventral skin surfaces. **A:** Mechanical thresholds of neuronal responses to stimulation of forepaw ventral skin (i.e. of *ventral* and *ventro-dorsal* RFs) obtained using von Frey monofilaments (bending pressures, g/mm²), taken as measures of neuronal response sensitivity. Boxplots represent first and third quartiles and medians. Statistical differences between the experimental groups and the CTRL group are indicated. \*: *p* < 0.05; \*:*: *p* < 0.01; \*:*:*: *p* < 0.001; \*:\*:\*: *p* < 0.0001.</figcaption></figure>

When considering the repartition of *simple*, *mixed*, and *paw* areas, we showed that their repartition depended upon the post-lesion time [F (12, 68) = 6.376, *p* < 0.0001] (Fig. 4C). We observed a significant decrease of the proportion of *simple* areas from the first hours post-lesion until the 14th post-lesion day, followed by a gradual return to normal [F (6, 34) = 7.39, *p* < 0.0001]. An inverse profile was observed for *mixed* [F (6, 34) = 5.527, *p* < 0.001] and *paw* areas [F (6, 34) = 4.85, *p* = 0.001]. Indeed, the reduction in relative size of *simple* areas in the whole cutaneous map (CTRL: 100 ± 0 %; D0: 76.88 ± 6.37 %, *p* < 0.0001; D7: 70.86 ± 6.17, *p* < 0.0001; D14: 75.17 ± 4.38, *p* < 0.0001) was related to a correlative appearance of *mixed* areas (CTRL: 0 ± 0 %; D0: 22.78 ± 6.27 %, *p* < 0.0001; D7: 25.38 ± 5.26 %, *p* < 0.0001; D14: 15.34 ± 5.63 %, *p* = 0.01) as well as *paw* areas where neurons displayed RFs spanning the whole ventral or dorsal skin surfaces of the paw (CTRL: 0 ± 0 %; D0: 0.34 ± 0.34 %, *p* = 0.878; D7: 3.76 ± 1.80 %, *p* = 0.091; D14: 9.50 ± 3.35 %, *p* < 0.001). This expansion reflects a dedifferentiation of the somatotopic maps. The repartition between *simple*, *mixed* and *paw* areas within the maps was reversed from D21, with a progressive increase of *simple* areas (D21: 82.97 ± 3.6 %, *p* = 0.01; D28: 95.47 ± 2.35 %, *p* = 0.420; D50: 93.81 ± 4.16 %, *p* = 0.393) at the expense of *mixed* (D21: 15.44 ± 2.40 %, *p* = 0.01; D28: 4.53 ± 2.35 %, *p* = 0.407; D50: 6.19 ± 4.16 %, *p* = 0.380) and *paw* areas (D21: 1.59 ± 1.59 %, *p* = 0.468; D28: 0 ± 0 %; D50: 0 ± 0 %) (Fig. 4C). The occurrence of the *mixed* and *paw* areas results from the merging of previously segregated representational zones.

## 3.3. Behavior

The sensorimotor deficits of the animals were evaluated using three different tests: the cylinder test to evaluate forepaw postural asymmetries, the ladder test to assess deficits in fine postural adjustments, and the adhesive tape test to measure impairments in tactile sensitivity.

Regarding the ladder test, we scored the rats' skills separately during upward and downward displacements. When considering upward displacement, we showed that the difference between the scores of the paretic and the non-paretic forepaws depend upon the post-lesion time [F (5, 94) = 3.167, *p* = 0.011]. The score of the non-paretic paw (represented in the mapped S1 cortex) was similar to the control values at each post-injury time tested [F (5, 42) = 2.13, *p* = 0.080; CTRL: 1.96 ± 0.01; D7: 1.91 ± 0.03; D14: 1.90 ± 0.03; D21: 1.93 ± 0.02; D28: 1.95 ± 0.01; D50: 1.99 ± 0.01] (Fig. 5A, see also Supplementary Fig. S1). However, the score of the paretic forepaw, represented in the ipsilesional cortex, decreased after the lesion, with a greater effect at the 7th post-lesion day, then increased until the 28th day, overall reflecting a mild sensorimotor impairment; scores obtained at the 50th post-lesion days suggest that animals had fully recovered from the lesion at this time point [F (5, 42) = 8.100, *p* < 0.0001; CTRL: 1.97 ± 0.01 %; D7: 1.76 ± 0.04, *p* < 0.0001; D14: 1.84 ± 0.03, *p* < 0.001; D21: 1.88 ± 0.03, *p* = 0.015; D28: 1.87 ± 0.02, *p* = 0.006; D50: 1.98 ± 0.01, *p* = 0.405] (Fig. 5A left).

During the downward displacement on the ladder, we observed no statistical difference between the score profiles of the paretic and the non-paretic forepaws over post-lesion time [F (5, 94) = 1.973, *p* = 0.090]. Interestingly, the score of the non-paretic paw significantly decreased, then slowly improved to return to pre-lesion values at the 50th day [F(5, 42) = 3.328, *p* = 0.013) (CTRL: 1.87 ± 0.03; D7: 1.72 ± 0.06, *p* = 0.02; D14: 1.64 ± 0.09, *p* < 0.001; D21: 1.71 ± 0.06, *p* = 0.014; D28: 1.67 ± 0.06; *p* = 0.002; D50: 1.92 ± 0.02; *p* = 0.15]. A similar score profile was observed for the paretic forepaw, but the deficits were even more accentuated. Indeed, the score strongly dropped during the first and second weeks, then slowly improved to return to pre-lesion values at the 50th day [F(5, 42) = 11.28, *p* < 0.0001; CTRL: 1.83 ± 0.04; D7: 1.45 ± 0.09, *p* < 0.0001; D14: 1.37 ± 0.07, *p* < 0.0001; D21: 1.56 ± 0.07, *p* < 0.001; D28: 1.57 ± 0.07, *p* < 0.001; D50: 1.86 ± 0.05, *p* = 0.062] (Fig. 5A, right).

The postural asymmetry index on the cylinder test diminished
<figure><img src="image_16.png" /><figcaption>**Fig. 4.** Remodeling of forepaw cutaneous representational maps after contralateral cortical injury. **A:** Representative electrophysiological cortical maps recorded from an intact rat (CTRL) and lesioned rats in which contralesional map was obtained at different post-injury time points. Note postlesion striking changes in the relative extent and topographic order of each representational zone, leading to a substantial dedifferentiation of the somatotopic maps. **B:** Boxplot showing the mean total size of the forepaw map in each experimental group (mm²). Boxplots illustrate the first and third quartiles, and the median values, while grey dots indicate individual map size values. **C:** Stacked histograms illustrating the relative mean areas of the different map regions, normalized with respect to the total forelimb cortical area. These relative areas are colour-coded (blue: simple area in which cutaneous RFs were confined on individual digits or plantar pads; red: mixed area corresponding to neurons with RFs localized on two or more forepaw skin subdivisions; orange: paw area in which RFs included the whole ventral or dorsal paw surface). Statistical differences between the experimental groups and the CTRL group are indicated for simple, mixed and paw areas. \*: p < 0.01; \*:*: p < 0.001; \*:\*:\*: p < 0.0001. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</figcaption></figure>

drastically after the injury with a minimum value at the 7th post-lesion day, meaning that the animals used almost exclusively their non-paretic paw during the raising behavior. The symmetry of forepaw use was progressively improved from the 14th to the 50th post-lesion day, but without reaching the pre-lesion value [F (5, 46) = 25.575, p < 0.0001; CTRL: 0.123 ± 0.20; D7: -0.79 ± 0.08, p < 0.0001; D14: -0.59 ± 0.12, p < 0.0001; D21: -0.47 ± 0.13, p < 0.0001; D28: -0.21 ± 0.11, p < 0.001; D50: -0.01 ± 0.14, p = 0.03] (Fig. 5B, supplementary Fig. S1).

For the adhesive removal test, the tactile sensitivity was assessed by the time needed for the animal to detect and remove the tape. The detection time for the paretic and the non-paretic forepaws displayed a different post-lesion time course [F (5,76) = 9.176, p < 0.0001]. After

the injury, the score recorded for the non-paretic forepaw remained unchanged at each post-lesion time point [F (5, 34) = 1.823, *p* = 0.135; CTRL: 4.24 ± 1.41 s; D7: 10.48 ± 5.28 s; D14: 8.88 ± 2.76 s; D21: 5.09 ± 2.39 s; D28: 4.69 ± 1.60 s; D50: 2.56 ± 0.59 s] (Fig. 5C, Supplementary Fig. S1). By contrast, the time of adhesive tape detection for the paretic forepaw greatly increased with a peak at the 7th post-lesion day, then gradually decreased until the 50th day where no significant difference with control values was found [F (5, 34) = 10.365, p < 0.0001; CTRL: 4.38 ± 0.77 s; D7: 72.32 ± 14.65 s, p < 0.001; D14: 67.16 ± 18.35 s, p < 0.001; D21: 41.62 ± 12.16 s, p < 0.01; D28: 25.91 ± 8.65 s, p < 0.01; D50: 2.91 ± 0.63 s, *p* = 0.397] (Fig. 5C).
<figure><img src="image_17.png" /><figcaption>**Fig. 5.** Behavioral assessment of sensorimotor deficits using the ladder, cylinder and adhesive removal tests. **A:** Scores obtained for the paretic (red) and non-paretic (green) forepaws during upward (left) and downward (right) displacements on the ladder, before and after the cortical lesion. **B:** Asymmetry index values obtained for the cylinder test before and after the lesion. **C:** Mean detection times (sec) obtained during the adhesive tape test before and after the injury for the affected forepaw (red) and the non-affected forepaw (green). Each dot shown corresponds to the mean value obtained throughout the preceding one-week testing session. The light-colored areas on both sides of the curves indicate the SEM. \* Statistical differences between mean data obtained before the lesion and at each postlesion time are indicated. \*\*: p < 0.05; \*\*: p < 0.01; \*\*\*: p < 0.001; \*\*\*\*: p < 0.0001. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)</figcaption></figure>

### 3.4. Lesion size evaluation

Evaluation of cortical lesion volume indicate no statistical difference between the lesioned experimental groups [F (4, 23) = 1.327, *p* = 0.290; D7: 1.80 ± 0.08 mm³; D14: 1.52 ± 0.16 mm³; D21: 1.33 ± 0.20 mm³; D28: 1.46 ± 0.12 mm³; D50: 1.44 ± 0.24 mm³] (supplementary Fig. S2).

### 4. Discussion

We presently investigated the time-course of remodeling occurring in the contralesional somatosensory cortex, as well as its role in functional recovery, which has long been overlooked in cortical lesion studies, where the vast majority of them focus on recovery of motor functions and correlative brain changes. Based on electrophysiological recording of small clusters of neurons in the S1 cortex, we demonstrate that a focal cortical injury to the forepaw area induces a substantial disorganization of the homologous representation of the non-paretic forepaw in the contralesional hemisphere. Notably, the lesion led to a drastic enlargement of the neuronal cutaneous RFs from the first post-lesion hours. This RF expansion reached a maximum value from the 7th to the 14th post-lesion day, while a gradual normalization of RF size observed thereafter was found to reach pre-lesion values at D50. Changes in neuronal sensitivity followed a similar time course, as neurons within the non-paretic forepaw area displayed a sensitivity to skin mechanical

stimulation that was greater from D0 to D14 and gradually returned to control values at D50. The marked RF enlargement led to a degradation of the spatial features of the forepaw representation, i.e. a dedifferentiation of the somatotopic organizational features of the cutaneous map. This disruption was drastic from D0 to D14, while a gradual, but still incomplete, somatotopic organization reemerged from D14 to D50. The overall surface area of the contralesional map was not found to be modified by the cortical lesion throughout the post-lesion period examined. Interestingly, these cortical changes evolved in parallel with sensorimotor deficits affecting both the ipsi- and contralesional forepaws. It is noteworthy that the fine postural adjustment capabilities of the non-paretic forepaw were significantly impaired, although less severely than in the paretic limb. It should be noted, however, that results at D50 should be considered with caution, given the small sample size at this post-lesional time.

#### 4.1. Cutaneous RF expansion in the "unaffected" S1 cortex and functional consequences

Our electrophysiological evaluation performed within the S1 forepaw area homologous to that of the lesioned cortical zone showed an immediate expansion of the neurons' cutaneous RFs along with an increased excitability, shown by an enhanced neuronal sensitivity to cutaneous stimulation. A substantial RF enlargement occurring in the area homologous to the lesioned zone in the contralesional cortex was
also reported in a study restricted to first 7 days after a focal ischemic lesion to the hindpaw representational zone (Reinecke et al., 2003). Interestingly, a decrease of GABAergic inhibition in contralesional cortex, related to a downregulation of GABA<sub>A</sub> receptors was observed during the first days post-lesion (Que et al., 1999; Redecker, 2002). This GABA<sub>A</sub> downregulation was also found in exofocal cortical areas, i.e. those adjacent to the ischemic zone, that reached a maximum at 3-7 days post-lesion, and declined to control levels after 14 days (Que et al., 1999). Along the same lines, a strong increase in the amplitude of evoked potential was recorded within the S1 area serving the contralateral hindpaw during the first hours following MCAO in rats (Sakatani et al., 1990). Furthermore, an expansion of cutaneous RFs in the S1 cortex was found whenever GABA-mediated local inhibition was antagonized (Alloway et al., 1989; Chowdhury and Rasmusson, 2002; Dykes et al., 1984; Tremere et al., 2001). Overall, these findings are consistent with the model of interhemispheric mutual inhibition, which stipulates that the hyperexcitability of the healthy cortex is related to the loss of inhibition normally exerted by the injured homotypic regions (Dancause and Nudo, 2011; Liepert et al., 2000; Dodd et al., 2017).

The increase in cutaneous RF size results from a broader recruitment of thalamocortical connections. The enlargement observed during the subsequent weeks after the lesion cannot be solely attributed to a disinhibition mechanism originating from the contralateral lesioned hemisphere. Indeed, changes in RF properties (location, size and responsiveness) of cortical map constituent neurons can be ascribed to alterations in the synaptic strength of subthreshold and suprathreshold inputs, ultimately converging onto cortical cells, as well as to alterations in the balance of excitatory and inhibitory influences through the thalamocortical and intracortical circuitry. These various mechanisms normally contribute to the segregation of synaptic inputs to cortical neurons. The unmasking of latent connections induced by synaptic strengthening of formerly ineffective synapses, i.e. that did not contribute to neuronal discharge (Jacobs and Donoghue, 1991; Malenka and Nicoll, 1997), is thought to be implicated in the experience-dependent plasticity of cortical neurons' RFs, via Hebbian mechanisms (Buonomano and Merzenich, 1998; Merzenich et al., 1987).

Numerous studies have underscored the influence of the temporal patterning, i.e. the degree of local synchrony of concurrent sensory inputs on the representational segregation of cortical somatosensory maps through receptive field remodeling (Allard et al., 1991; Byl et al., 1996; Diamond et al., 1993; Godde et al., 1996; Recanzone et al., 1992a; Rosselet et al., 2008; Wang et al., 1995; Zennou-Azogui et al., 2016). A consistent finding in all these studies was that temporally synchronized stimulation of large skin territories induced RF enlargement, whereas temporally distributed skin stimulation resulted in RF sharpening. In monkeys trained on a frequency-discrimination task that involved repeated tactile stimulation of a constant digit skin locus, the RFs of area 3b neurons of S1 serving the trained skin became much larger and included part of the adjacent, apparently non-stimulated skin surfaces of the digit (Recanzone et al., 1992c; Xerri et al., 1999). On the contrary, tactile stimuli delivered asynchronously across the digit skin induced a reduction in the size of the RFs restricted to the trained skin surfaces (Jenkins et al., 1990; Xerri et al., 1999). Furthermore, after a behavioral training with sequences of tactile stimuli applied simultaneously across the ventral side of adjacent digits, area 3b neurons that normally exhibit single RFs displayed multiple RFs on the glabrous skin surfaces of these trained digits and an enlargement of the glabrous RFs on the simultaneously stimulated glabrous surfaces of these digits (Wang et al., 1995). Along the same line, associative pairing of tactile stimuli applied to two distinct skin sites of the rat hindlimb (toes, or a toe and palmar pad) induced an expansion of the RFs on the stimulated skin territories (Godde et al., 1996). Moreover, electrical stimulation of the dorsal branch of the cubital nerve, which massively recruits afferent fibers was found to dramatically enlarged the RFs of area 3b neurons in the cortical sectors representing the skin surfaces innervated by the dorsal branch (Recanzone et al., 1990).

All these studies argued for the critical role of input timing in determining cortical map topologies and spatial resolution, since the enlargement of S1 neurons' RFs was induced by increasing the number of concurrent inputs generated by intensive training or electrical stimulation and delivered nearly synchronously to the cortex. It is noteworthy that recordings in the ventroposterior nucleus of the thalamus indicate that these RF changes were primarily cortical (Wang et al., 1995) as also shown by intracortical stimulation studies (Recanzone et al., 1992b; Spengler and Dinse, 1994). Based on these findings, one can propose that the RF enlargement observed for neurons in the S1 area serving the non-paretic forelimb can be ascribed to a broader simultaneous contact of the corresponding forepaw ventral skin surfaces with the cage floor during stance and locomotion. This interpretation is supported by an earlier study, in which we performed severe sensorimotor deprivation by using single-forelimb casting in rats. This procedure led to an over-reliance on the non-constrained forelimb for postural balance and increased mechanical pressure on the ventral skin surfaces of the uncast forepaw (Coq and Xerri, 1999b). The forced use of the non-cast forelimb did not affect the area of the corresponding cutaneous map, as also found in the present study, but it led to a substantial enlargement of glabrous skin RF. Similarly, in the present study, over-reliance on the non-paretic forelimb combined with a decreased use of the paretic forepaw may have led to an increased use of the former to maintain postural balance and contact with supporting surfaces. This was attested by the rats' asymmetrical positioning of the forepaws on the cylinder walls during upright stance. One can thus hypothesize that changes in functional use of the forepaws in the rat's behavioral repertoire were more likely to generate cutaneous inputs spatially less restricted on a particular glabrous skin region of the non-paretic forepaw and temporally more coherent because of the simultaneous stimulation of larger than usual glabrous skin territories during postural support. Accordingly, the RF enlargement very likely resulted from a fusion of previously segregated RF, i.e. from the spatial aggregation of thalamocortical inputs through unmasking/strengthening of formerly subthreshold synapses. This RF aggregation induced a degradation of spatial selectivity of the corresponding cortical neurons, a disruption of the normal separation between glabrous ventral and hairy dorsal representational zones, so that the topographic organization of the non-paretic forepaw map became drastically dedifferentiated.

## 4.2. Remodeling of contralesional areas evolves in parallel with functional recovery

The deterioration of the non-paretic forepaw map raises the question of its possible behavioral consequences. We found that the rats' performance on the ladder test (mostly during downward displacement) was severely impaired, not only because of the poor performance of the paretic forepaw, but also as a result of the significantly degraded performance of the non-paretic limb. It is very likely that the RF expansion and degraded cortical map somatotopy induced a significant impairment of tactile acuity of the non-paretic forepaw. This is a plausible explanation for the degradation of tactile spatial acuity that impairs the unaffected limb in stroke patients (Carey and Matyas, 2011). We reasoned that degraded tactile acuity would impact the ability to generate the fine sensorimotor adjustments required to successfully perform on the tilted-ladder test. Alternatively, deficits affecting the fine sensorimotor skills of the non-paretic forelimb may, at least in part, be explained by the postural asymmetries due the impairment of the paretic forepaw. One may consider that these asymmetries increased the functional demand on the non-paretic limb to maintain postural stability, thus compromising the sensorimotor capacities of the non-paretic forelimb. Along this line of reasoning, the functional restoration of these capacities might be attributed to a relearning process through which the rats would gradually cope with the demanding sensorimotor adjustments inherent to the ladder test. Within this frame of interpretation, the gradual normalization of neuronal RF sizes in the non-paretic
representational zone would result from a sensorimotor relearning through cutaneous inputs asynchronously delivered to the cortex.

At post-lesion day 50, there was no differences between affected and non-affected forepaw performances in the ladder and adhesive removal tests suggesting substantial compensation of fine sensorimotor deficits. However, the slight persistent asymmetry observed in the cylinder test indicates ongoing impairments in spontaneous use of the affected limb. These findings could be explained by a dissociation between task-driven and spontaneous limb use, suggesting that while some deficits may be fully compensated in specific attention-demanding settings, not all facets of function, particularly spontaneous limb use, are fully restored. In line with our results, using enriched rehabilitation regimens designed to encourage affected limb use, *Biernaskie and Corbett* (2001) found that a notable reliance on the unaffected forelimb can persist for weeks after injury, as detected by the cylinder test, while recovered motor function was observed on reaching and beam-walking tests.

We found that the time course of recovery for both sensorimotor abilities and tactile sensitivity of the paretic forepaw evolved in parallel with that of the changes affecting the cutaneous RFs and cortical map organizational features of the non-paretic forepaw. At D50 the threshold of excitability, as well as the RF size and the organization of contralesional cutaneous maps, were found to be similar to those observed in control animals, thus indicating that the functional recovery was complete or nearly complete. Normalization of contralesional neuronal properties is likely to depend upon a significant reactivation of the ipsilesional cortex, as suggested by transcranial magnetic stimulation (TMS) or transcranial direct current stimulation aimed at improving motor recovery in stroke patients by restoring an interhemispheric balance (van Meer et al., 2010, 2012). It is worth mentioning that there is a consensus in the literature on the importance of a refocusing of activation in the ipsilesional cortex, and mainly the perilesional areas, alongside a decrease in the hyperactivity of the intact cortex, in order to observe a more complete functional recovery of manual skills (Calautti et al., 2010; Grefkes and Fink, 2014; Grefkes and Ward, 2014).

However, there is a need to reevaluate the interhemispheric competition model initially proposed by Cook in 1984, as it does not exhaustively account for clinical observations in stroke patients. For instance, in stroke survivors with upper extremity somatosensory loss, short-term application of facilitatory high-frequency rTMS (5 Hz) to the contralesional S1 combined with peripheral somatosensory stimulation, has been found to promote somatosensory function (Pundik et al., 2021). It's of interest that a recently proposed explanatory model of interhemispheric interplay according to which the two hemispheres do not simply compete through crossed inhibitory influences, but rather constantly integrate information *via* both excitatory and inhibitory interactions (Brancaccio et al., 2022).

### 4.3. Possible origins of the normalization of neuronal response properties in the contralesional hemisphere

The refocusing of cortical activation towards perilesional areas, a process considered as crucial for optimal recovery of sensorimotor deficits, has been confirmed in rats (Dijkhuizen et al., 2003). In our study, we performed further exploratory recordings in the injured cortex at D28 in 3 animals (data not shown). During these mapping sessions, we did not find any cortical responses evoked by cutaneous or proprioceptive stimulation of the paretic forepaw in the perilesional areas and more distant areas, likely because our lesions were too extensive to allow somatosensory reactivation in these cortical regions. Therefore, one can raise the question of the source of neurophysiological influences leading to a gradual normalization of the non-paretic forepaw RFs and somatotopic representation.

Theoretically, one cannot discard the possibility that unmasking of cutaneous afferents originating from the paretic forepaw and conveyed through an ipsilateral pathway to the contralesional cortex could have contributed to the functional recovery of tactile sensitivity and

sensorimotor abilities of the contralesional forepaw. This explanation would be consistent with studies showing the existence of an ipsilateral representation in S1, either in intact rodents using voltage sensitive dye imaging, which mostly reveals activity induced by subthreshold inputs (Ferezou et al., 2007; Mohajerani et al., 2011; Morales-Botello et al., 2012) or in humans in somatosensory evoked potential electroencephalography recordings, functional magnetic resonance imaging (fMRI), and magnetoencephalography studies (Allison et al., 1989; Korvenoja et al., 1999; Nihashi et al., 2005). In our study, we searched for cutaneous responses evoked by stimulation of the ipsilateral paretic forepaw, but we found no evidence for such responses in the cortical zones neighboring the representational area of the non-paretic forepaw. It is notable that other studies using fMRI (Abo et al., 2001; Dijkhuizen et al., 2001) and intrinsic optical imaging (Johnstone et al., 2013) did not find the existence of an ipsilateral representation in rodents. The mechanisms underlying the normalization of the cutaneous RFs, neuronal sensitivity and somatotopic organization within the non-paretic limb representational area remains to be demonstrated. It cannot be explained by an ipsilateral representation of the paretic forepaw, unless such a representation could exert an inhibitory influence onto the neurons receiving inputs from the non-paretic forepaw leading to a RF sharpening. Reasoning within the framework of post-lesion adaptive changes in crosstalk between homotypic cortical areas, it is conceivable that changes in interhemispheric communication accounting for our cortical map findings occurred through subcortical circuits shaping the response properties of cortical neurons. Interestingly, cortico-cortical communication can occur through trans-thalamic pathways (Mo and Sherman, 2019). Neuro-anatomical tracing studies in rodents (Battaglia et al., 1994; Rao's and Bentivoglio, 1993), confirmed by electrophysiological evidence (Timofeev and Steriade, 1996) provide a substrate for thalamic nuclei interrelations through reticular nuclei that allow to bridge both hemispheres. An increase in discharge frequency of reticular (RT) neurons resulting from ministroke to the ipsilateral S1 cortex leads to an enhanced inhibition exerted onto both the contralateral RT neurons and ipsilesional ventro-postero-lateral (VPL) thalamic nucleus. These effects result in a decreased interhemispheric inhibition on the RT neurons in the contralesional side and also translate into a reduction of inhibition normally exerted by the VPL on its contralateral counterpart (Frost et al., 2003; Murphy and Corbett, 2009). Hence, the enhanced excitability of thalamic cortical pathways contralateral to stroke which relay somatosensory afferents from the non-paretic forepaw may be mediated by a rearrangement of sensory processing through thalamic nuclei leading to a modification of the balance of interhemispheric inhibitory influences (Mohajerani et al., 2011).

Neuroimaging studies in stroke patients have led to the consensus that optimal functional recovery occurs in individuals displaying relatively nearly normal patterns of sensory and motor activation within the lesioned cortex. In contrast, those with larger stroke damage usually continue to display bilateral hemispheric activations and show a less positive clinical outcome (Rehme et al., 2011; Schaechter et al., 2006; Ward et al., 2003). The normalization of S1 neurons response characteristics occurring in parallel with the recovery of sensorimotor abilities reported in the present study may reflect the efficiency of compensatory mechanisms presumably involving changes in interhemispheric communication between sensorimotor cortical networks. Although functionally adaptive redistribution of interhemispheric activity could arise in the absence of changes in structural connectivity, one cannot rule out that structural changes in long-range projections contribute to altered sensory processing underlying the recovery of sensorimotor skills following cortical damage.

Supplementary data to this article can be found online at https://doi.org/10.1016/j.nbd.2025.107043.

### CRediT authorship contribution statement

Justine Facchini: Writing – review & editing, Writing – original
draft, Validation, Methodology, Investigation, Formal analysis. **Christian Xerri:** Writing – review & editing, Validation, Methodology, Investigation, Formal analysis, Conceptualization. **Abdessadek El Ahmadi:** Writing – review & editing, Validation, Formal analysis. **Isabelle Watabe:** Investigation. **Nicolas Catz:** Software. **Yoh'i Zennou-Azogui:** Writing – review & editing, Validation, Supervision, Project administration, Methodology, Investigation, Data curation, Conceptualization.

## Funding sources

This research was supported by grants from the Ministère de l'Enseignement Supérieur et de la Recherche and CNRS (UMR 7077, Aix-Marseille Université).

## Declaration of competing interest

The authors declare no competing interests.

## Acknowledgments

We thank Elodie Mansour and Jean Luc Fina for taking care of the animals, and Sabine Quitard for her helpful assistance during the assessment of lesion size. We would also like to thank Dr. Rochelle Ackerley for proofreading the manuscript and correcting the English.

## Data availability

Data will be made available on request.

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