domain: scco sdv

text:
MD Elise Barois

PhD Yoshimasa Sagawa

MD Suveyla Yilmaz

MD, PhD Eloi Magnin

MD, PhD Pierre Decavel
email: pierre.decavel@univ-fcomte.fr

What (more) can verbal fluency tell us about multiple sclerosis?

Keywords: multiple sclerosis, verbal fluencies, cognitive impairment

Background. Clinical symptoms of multiple sclerosis (MS) are variable and may include cognitive impairment, which can be assessed with the verbal fluency test (VFT). This test is evaluated by counting words spoken during a 2-min period, which is not a functional approach.

Ojbective. The objectives of this observational study were to 1) determine new parameters that reflect communication and cognitive functions in persons with multiple sclerosis (PwMS) considering the evaluation of real-time word production in the VFT; 2) compare the results with those of a control group; and 3) evaluate the impact of including errors.

Methods.

A phonological fluency test ("letter P") and a semantic fluency test ("animals") were used. The real-time word production was recorded. The main variables studied were the total number of words, first word delay, moment of inflection of the curve corresponding to the change in the cognitive process, speed of word production before inflection, and maximum delay between 2 consecutive words. These variables were studied by taking into account or not errors.

Results. We included 68 PwMS and 33 healthy controls. VFT results were impaired in PwMS. The total number of words, first word delay, speed before inflection, and maximum delay were relevant to the study of phonologic fluency. For studying semantic fluency, the total number of words, first word delay, speed before inflection, and inflection time of the curve seemed relevant. Taking into account errors was significant only for total number of words.

Conclusion.

Taking into account errors in evaluating real-time word production in PwMS is of interest only for the total number of words performed but has no impact on the variables studied. These variables should be used to quantitatively evaluate verbal fluency with the objective of evaluating functionally relevant parameters (communication).

Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system.

Clinical symptoms of MS are variable but may often include cognitive impairment [START_REF] Islas | Assessment and Impact of Cognitive Impairment in Multiple Sclerosis: An Overview[END_REF]. Indeed, cognitive impairment is described in 40% to 70% of persons with multiple sclerosis (PwMS) [START_REF] Digiuseppe | Short Report: Prevalence of Cognitive Impairment in Newly Diagnosed Relapsing-Remitting Multiple Sclerosis[END_REF] in all forms and at all stages of the disease and even at a preclinical stage such as isolated clinical syndrome in which cognitive disorders can affect 12% to 80% of patients [START_REF] Potagas | Cognitive impairment in different MS subtypes and clinically isolated syndromes[END_REF][START_REF] Anhoque | Cognitive impairment in clinically isolated syndrome: A systematic review[END_REF] The most affected and most-studied cognitive domains are episodic memory and information-processing speed [START_REF] Chiaravalloti | Cognitive impairment in multiple sclerosis[END_REF]. Working memory, executive function, attention, language, and, more recently, social cognition are other affected domains that have been investigated in PwMS [START_REF] Chiaravalloti | Cognitive impairment in multiple sclerosis[END_REF][START_REF] Cotter | Social cognition in multiple sclerosis: A systematic review and meta-analysis[END_REF]. These alterations lead to negative repercussions on daily living activities [START_REF] Rao | Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction[END_REF], social life, and quality of life [START_REF] Clemens | How does cognition relate to employment in multiple sclerosis? A systematic review[END_REF] of PwMS.

The first step in managing cognitive impairment in PwMs is its identification and quantification. Batteries of cognitive tests for PwMS exist, but they are difficult to administer in standard consultation except for the Brief International Cognitive Assessment for MS (BICAMS), which offers a feasible, cost-effective means of assessing cognition [START_REF] Benedict | Brief International Cognitive Assessment for MS (BICAMS): international standards for validation[END_REF][START_REF] Corfield | A Systematic Review and Meta-Analysis of the Brief Cognitive Assessment for Multiple Sclerosis (BICAMS)[END_REF].

Among the multiple tests used for these purposes, the verbal fluency test (VFT) is of interest for several reasons. The VFT reflects multifactorial demands such as lexical and semantic stores and executive functions that control and program verbal production, activity planning, organization of responses, elimination of previously cited responses, and access to the mental lexicon [START_REF] Magnin | Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis[END_REF]. The VFT is easy and short to administer, and the clinician does not have to depend on diagnostic equipment or require special training [START_REF] Thiele | New ways to analyze word generation performance in brain injury: A systematic review and meta-analysis of additional performance measures[END_REF]. The VFT is also reliable, even for severe forms of MS [START_REF] Vlaar | Verbal fluency assessment of patients with multiple sclerosis: test-retest and inter-observer reliability[END_REF], and it is a sensitive indicator of brain impairment [START_REF] Thiele | New ways to analyze word generation performance in brain injury: A systematic review and meta-analysis of additional performance measures[END_REF] that has been found effective in assessing cognitive impairment with sensitivity and specificity of 80.6% and 97.2% [START_REF] Negreiros | A brief neuropsychological screening test battery for cognitive dysfunction in Brazilian multiple sclerosis patients[END_REF].

Phonologic (e.g., letter "p") and semantic (e.g., "animals") fluencies are the most common tests [START_REF] Henry | Verbal fluency performance in dementia of the Alzheimer's type: a meta-analysis[END_REF]. Phonological fluency is more closely associated with phonologic memory and requires the creation of uncommon word-recall strategies based on their lexical features and suppressing meaning-based responses. In turn, semantic fluency is more closely associated with semantic stock and the property of grouping named objects into categories [START_REF] Tupak | Differential prefrontal and frontotemporal oxygenation patterns during phonemic and semantic verbal fluency[END_REF]. Phonologic fluency seems to have a larger executive component than semantic fluency [START_REF] Magnin | Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis[END_REF]. Data from functional brain imaging showed that semantic fluency tasks are temporally lobe-dependent, whereas phonologic fluency depends more on the frontal lobe [START_REF] Biesbroek | Shared and distinct anatomical correlates of semantic and phonemic fluency revealed by lesion-symptom mapping in patients with ischemic stroke[END_REF].

To perform the VFT, participants are required to generate as many words as possible within a fixed period of time in accordance with specific instructions. Usually, the quantitative analysis of the performance in VFT is the correct number of words [START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level][END_REF]. This parameter is useful for showing an increase in cognitive function after treatment [START_REF] Magnin | Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis[END_REF], but the average improvement of 2 words in 2 min on phonologic fluency does not reflect a functional impact on PwMS. This one is reflected by communication disorders, which depends on a number of factors including cognitive skills, especially verbal function [START_REF] Yorkston | Communicative participation restrictions in multiple sclerosis: Associated variables and correlation with social functioning[END_REF].

Regarding the words produced during a specified time frame, some authors have been interested in the delay of a word response. The first of these researchers was Bousfield et al. in 1944 [20]. However, the concept was actually developed by [START_REF] Rohrer | Retrieval from semantic memory and its implications for Alzheimer's disease[END_REF] patients with Alzheimer disease. The authors developed 2 parameters to analyse verbal fluencies: the number of words produced and the mean number of words produced in 5 sec [START_REF] Rohrer | Retrieval from semantic memory and its implications for Alzheimer's disease[END_REF]. They also described the decrease in words produced during the test. Crowe et al. divided the time by 15 sec [START_REF] Crowe | Decrease in performance on the verbal fluency test as a function of time: evaluation in a young healthy sample[END_REF]. The authors observed a larger production of words during the first 15 sec with a great frequency of occurrence of words. This production profile suggests that the initial responses depend on rapid access to the lexico-semantic stock, which requires little effort. For later production, lexico-semantic stock search strategies are set up, with executive function [START_REF] Lezak | Neuropsychological Assessment[END_REF]. Collectively, these results suggest that in addition to the number of correct words produced during a specified period [START_REF] Magnin | Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis[END_REF][START_REF] Negreiros | A brief neuropsychological screening test battery for cognitive dysfunction in Brazilian multiple sclerosis patients[END_REF], other analyses could provide new information about cognitive impairment in PwMS. Moreover, errors are not taken into account in the fluency assessment [START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level][END_REF]. Different types of errors can occur when the VTF is administered, such as the rule break error (e.g., words out of category), repetitions (e.g., words already generated that are produced again), and non-item production (e.g., interjections such as "um") [START_REF] Thiele | New ways to analyze word generation performance in brain injury: A systematic review and meta-analysis of additional performance measures[END_REF]. These errors may be considered a lack of inhibition and an inability to resist irrelevant information [START_REF] Kavé | Cognitive Correlates of Perseverations in Individuals with Memory Impairment[END_REF][START_REF] Saa | Longitudinal evaluation of cognition after stroke -A systematic scoping review[END_REF].

To our knowledge, no study has explored production in real time during the VFT in PwMS. This study aimed to 1) find new parameters that reflect communication and cognitive functions in PwMS, considering the evaluation of real-time word production measured with the VFT; 2) compare the results with those of a control group; and 3) evaluate the impact of including errors in the analysis.

Methods

Study design

This observational study was conducted at the University Hospital of Besançon. This study is a part of a clinical trial designed to evaluate the impact of fampridine on the functionality of PwMS. It was approved by the French national ethics committee (no. 13/405) and by the French Health Products Safety Agency (no. 2013-A002305-56) and was registered at ClinicalTrials.gov (NCT02849782).

Participants

A group of PwMS and healthy individuals (controls) participated in this study. All participants were recruited during their usual ambulatory consultation in the departments of Physical Medicine and Rehabilitation and Neurology of the hospital between 2014 and 2019.

The inclusion criteria for PwMs depended on the initial protocol focused on the clinical gait analysis and were 1) age 18 to 80 years, 2) MS diagnosis based on the modified

McDonald criteria [START_REF] Polman | Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria[END_REF], 3) Expanded Disability Status Scale (EDSS) score 4.0 to 6.5, and 4) able to walk for at least 6 min. The exclusion criteria were 1) worsening MS symptoms during the previous 60 days, 2) immunotherapy change in the previous 60 days, 3) initiation of treatment to decrease fatigue symptoms in the previous 30 days, and 4) modification of the rehabilitation program during the study.

For controls, inclusion criteria were men and women aged 18 to 80 years and affiliated with the French social security system. The exclusion criteria were motor or neurologic deficits that could interfere with cognition. All participant underwent assessments. Written informed consent was obtained from all participants.

Evaluations Participant characteristics

A practitioner examined all participants to check for inclusion and exclusion criteria and to collect characteristics (i.e., age, sex, height, weight, body mass index [BMI], disease duration, EDSS, and MS type).

The impact of fatigue on participants was assessed with the Fatigue Impact Scale (FIS) [START_REF] Fisk | Measuring the Functional Impact of Fatigue: Initial Validation of the Fatigue Impact Scale[END_REF] measured in 3 domains: cognitive (10 items), physical (10 items), and psychosocial (20 items). The FIS is a self-assessment survey in which participants score the impact of fatigue in specific situations (0 = no problem, 4 = extreme problem), for a total score of 160. A high score indicates greater impact of fatigue. This is the only scale of fatigue assessment for PwMS validated in French [START_REF] Debouverie | Validity of a French version of the fatigue impact scale in multiple sclerosis[END_REF]. The FIS showed a good construct validity (Cronbach α > 0.87) [START_REF] Fisk | Measuring the Functional Impact of Fatigue: Initial Validation of the Fatigue Impact Scale[END_REF] and reliability (intraclass correlation coefficient 0.68-0.85) [START_REF] Mathiowetz | Test-retest reliability and convergent validity of the Fatigue Impact Scale for persons with multiple sclerosis[END_REF] in PwMS.

Information-processing speed was assessed with the Symbol Digit Modalities Test (SDMT) [START_REF] Benedict | Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis[END_REF][START_REF] Smith | Symbol Digit Modalities Test (SDMT) Manual[END_REF], which consists of a legend at the top of the page with 9 symbols and 9 equivalent numbers (from 1 to 9), and several lines with these symbols are depicted in a random order. During the test, participants are required to fill in correctly, as much as possible, the lines with the correct corresponding number in 90 sec. A higher score indicates better cognitive abilities. The SDMT has sensitivity of 74% and specificity of 76% for detecting cognitive impairment in MS [START_REF] Deloire | How to detect cognitive dysfunction at early stages of multiple sclerosis?[END_REF]. The SDMT is reliable and has good to excellent reproducibility [START_REF] Morrow | Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks[END_REF].

Verbal fluency

Cognitive impairment was assessed with the VFT. The tests were performed in a quiet room with a voice recorder. The participants were asked to provide as many words as possible in 2 min without making mistakes and without repeating themselves (cf. posttreatment below). For methodologic considerations (e.g., good performance in healthy population), we used the letter "P" for phonologic fluency and the category "animals" for semantic fluency [START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level][END_REF].

Afterward, SPPAS, a free software (http://www.sppas.org/), was used to segment the audio track in accordance with the words produced by the participants. SPPAS allows for knowing the beginning and end of the production of each word with accuracy of 1 msec [START_REF] Bigi | SPeech Phonetization Alignment and Syllabification (SPPAS): a tool for the automatic analysis of speech prosody[END_REF][START_REF] Bigi | Automatic Segmentation of Spontaneous Speech / Segmentação automática da fala espontânea[END_REF]. After this phase, we listened to all fragments to confirm, identify, and transcribe the words into a spreadsheet (Microsoft Excel). The accounting of errors followed the criteria used by Cardebat et al. and St-Hilaire et al. [START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level][END_REF][START_REF] St-Hilaire | Normative data for phonemic and semantic verbal fluency test in the adult French-Quebec population and validation study in Alzheimer's disease and depression[END_REF]. For both phonologic and semantic fluency tests, repetition was defined as the same word produced identically one or more times and was considered an error. For phonologic fluency, the following conditions were considered errors: proper nouns; different morphologic forms of a verb, noun, or adjective (e.g., prince, princesse; petit, petite); nonwords; and words that do not start with the desired letter. Anglicisms and words with the same etymologic root, explaining that they referred to distinct concepts (e.g., tableau, tablette), were accepted. For words with a similar pronunciation, the second use was considered a repetition unless the participant spontaneously explained the meaning of the word or spelled the 2 words.

For semantic fluency, the following conditions were considered errors: declension of a subcategory of animals (e.g., caniche, dogue, teckel), non-words, a word that does not mean an animal, and the morphologic derivations of a word (e.g., lion, lionne, lionceau). The name of the female or the name of the young of an animal was counted if it was expressed with a different word.

In addition to 1) the total number of words currently used to assess the cognition of PwMS, the following variables were retained for each type of fluency (Fig. 1): 2) first word delay (seconds), which corresponds to the delay between the end of the instruction and the beginning of the first word (first word delay includes the processing of the retrieval cue and the initiation of the search process [START_REF] Rohrer | Retrieval from semantic memory and its implications for Alzheimer's disease[END_REF]); 3) inflection time (seconds), which corresponds to the time of the first break in the curve determined from the interval higher than 2 standard deviations (SDs) of the intervals (inflection time corresponds to the moment when the cognitive process changes from fast access to the semantic stock to search strategies in semantic memory, in relation to the executive functions [START_REF] Lezak | Neuropsychological Assessment[END_REF]); 4) number of words produced before the inflection of the curve, which corresponds to the semantic stock [START_REF] Lezak | Neuropsychological Assessment[END_REF]; 5) speed before inflection (number/seconds), which corresponds to the speed of word production before inflection of the curve; and 6) maximum delay (seconds), which corresponds to the highest interval between producing 2 consecutive words. Maximum delay gives a more precise description of the recovery process itself [START_REF] Rohrer | Retrieval from semantic memory and its implications for Alzheimer's disease[END_REF].

Procedures

The evaluation was performed in a single day at the Clinical Functional Exploration Laboratory of the Movement. First, a practitioner checked the inclusion and exclusion criteria and examined all participants to collect their characteristics. After that, participants answered the FIS and SDMT. Then, the phonologic fluency test was performed, followed by the semantic fluency test. The control group underwent the same evaluation procedure, under the same conditions as the PwMS, except for the specific tests regarding MS (i.e., disease duration, EDSS, and MS type).

Analyses

Data management and analyses involved using Statistica v10 (StatSoft, USA). The results are expressed as mean (SD). Participants' characteristics were compared, when appropriate, by independent Student t test or chi-square test. To compare PwMS and the control group (between-factor) and fluencies with or without errors (within-factor) for all fluency variables, 2-way ANOVA was performed. Only the main effects (i.e., the group effect and with or without fluency errors) were considered in this study. P< 0.05 was considered statistically significant.

Results

We included 68 PwMS and 33 healthy individuals. Table 1 presents the participants' characteristics. We found no significant difference between the groups in terms of age, sex, height, weight, or BMI. For PwMS, the mean disease duration was 14.5 (10.4) years and the mean EDSS score was 5.2 (1.1). Secondary progressive MS was the main form (48.5%) followed by the primary progressive (30.9%) and relapsing-remitting (20.6%) forms. The groups differed in FIS and SDMT scores (both p < 0.001). Figure 2 shows an example of time of word production for semantic and phonologic fluency tests for a participant in each group. Verbal fluencies were variable among participants for both tests. For phonologic fluency, word production for PwMS ranged from 5 to 33 words but from 8 to 39 for controls. For semantic fluency, word production for PwMS ranged from 5 to 42 words but from 18 to 50 for controls.

Table 2 shows the mean (SD) values for all verbal fluency variables studied and comparisons between groups and considering or not the errors in word production. By comparing the results of word production for the conditions with or without error, we found a significant difference only for total number of words, lower in the "non-error" group (phonologic: p < 0.001; semantic p = 0.023).

PwMS and controls did not differ in proportion of errors as compared with total number of words. The groups differed for most of the variables studied, for both phonologic and semantic fluency. The first-word delay and the maximum delay were higher for PwMS than controls and the total number of words, inflexion time, inflexion words, and speed before inflexion were lower. The groups differed in inflection time for semantic fluency (p = 0.002) but not phonologic fluency (p = 0.061), and values were reversed as compared with semantic fluency: inflection time was later for PwMS than controls.

The speed before inflection was slower for PwMS than controls for both semantic and phonologic fluency (p < 0.001).

Discussion

We aimed to find potential new variables to evaluate cognitive impairments in the VFT for PwMS and controls. We took into account other variables reflecting word pattern production as well as the impact of the errors produced during this task. The use of the new variables previously cited provides a more complete clinical interpretation of the VTF, and the development of new processing software allows for precisely knowing the time of word production.

Batteries of cognitive tests in the MS have several tests in common, but a core battery termed the Minimal Assessment of Cognitive Function in MS (MACFIMS) evaluates the most domains (attention, working memory, executive functions, verbal and spatial episodic memory, language, spatial processing of information) [START_REF] Benedict | Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS)[END_REF]. However, it does not include semantic fluency. It requires 90 min to complete and is not feasible to administer during a standard consultation. The Brief International Cognitive Assessment for MS (BICAMS) has been proposed as an evaluation tool for practitioners [START_REF] Benedict | Brief International Cognitive Assessment for MS (BICAMS): international standards for validation[END_REF]. It consists of 3 tests: SDMT, the first 5 reminders of the California Verbal Memory Test-II for verbal memory, and the first 3 reminders of the Brief Visual Memory Test-R for visual-spatial episodic memory. However, the BICAMS does not include a test for evaluating executive function or language.

Information-processing speed can be evaluated by the SDMT [START_REF] Smith | Symbol Digit Modalities Test (SDMT) Manual[END_REF]. Executive functions and semantic memory can be evaluated by the VFT, which has another advantage: the absence of the use of upper-limb motricity. These 2 types of tests could be a complementary and rapid way to evaluate the cognitive function of MS patients.

Usually, the VFT analysis does not take into account errors. Taking into account errors significantly modifies only the total number of words produced and has no impact on the variables we decided to study with a pure quantitative approach. The error rate has been found to increase switching for patients with a frontal lobe lesion, which manages inhibition capabilities [START_REF] Troyer | Clustering and switching on verbal fluency: the effects of focal frontal-and temporal-lobe lesions[END_REF]. However, in our study, the percentage of errors was not higher for PwMS than controls and seems not a criterion to detect executive dysfunction.

We found an increase in the first word delay for PwMS as compared with controls for both semantic and phonologic fluencies. A decrease in the speed of information processing may explain this finding of a lack of initiation in the 2 types of fluencies [START_REF] Glanz | Cognitive deterioration in patients with early multiple sclerosis: a 5-year study[END_REF]. This parameter is interesting because it is totally independent of motor processing such as dysarthria; patients have not started word production during this period. This slowness in starting a verbal activity could have a social impact by making the beginning of a conversation more difficult and can therefore decrease repartee [START_REF] Feenaughty | Separate and Combined Influence of Cognitive Impairment and Dysarthria on Functional Communication in Multiple Sclerosis[END_REF]. Feenaughty et al. [START_REF] Feenaughty | Separate and Combined Influence of Cognitive Impairment and Dysarthria on Functional Communication in Multiple Sclerosis[END_REF] showed a correlation between speech disorders and communication.

Another parameter highlighted is the first inflection time of the curve. The inflection of a curve suggests a cognitive process change [START_REF] Lezak | Neuropsychological Assessment[END_REF], from fast access to the semantic stock to search strategies in semantic memory, in relation to executive functions. For phonologic fluency, the first inflection time did not differ between PwMS and controls (p = 0.061).

Indeed, the moment of cognitive process change cannot be highlighted because participants may use their executive abilities from the beginning of the test, as shown by the low speed before inflection [START_REF] Magnin | Verbal Fluencies and Fampridine Treatment in Multiple Sclerosis[END_REF]. Conversely, for semantic fluency, the inflection of the curve occurs earlier for PwMS. Abad et al. [START_REF] Abad | The analysis of semantic networks in multiple sclerosis identifies preferential damage of long-range connectivity[END_REF] studied semantic networks in PwMS: during the qualitative analysis of these networks, damage occurred in connectivity between words for PwMS. As a result, the speed of word production was slower and the semantic stock depleted more quickly for PwMS.

The maximum delay between 2 consecutive words was higher for PwMS than controls only for the phonologic fluency tests. The maximum delay corresponds to the duration of the recovery process [START_REF] Rohrer | Retrieval from semantic memory and its implications for Alzheimer's disease[END_REF], which requires the use of executive functions. Because phonologic fluency depends mainly on executive functions, the maximum delay between 2 words is longer for PwMS than controls if these functions are reached.

The total number of words, first word delay, speed before inflection, and maximum delay are relevant to the study of phonologic fluency. For the study of semantic fluency, the total number of words, first word delay, speed before inflection, and inflection time of the curve could be used. These variables, easy to collect over the consultation time, provide relevant clinical data on the executive function in PwMS and should be used to quantitatively evaluate verbal fluencies with the additional objective of evaluating functional parameters (communication).

We propose adding VFT to the BICAMS, using only animals and the letter "p" (in French language) and using the analysis proposed in this paper. This addition will allow for building a more complete battery of tests, including executive function assessment and an overview of communication, while remaining within 20 min completion time, including instructions [START_REF] Corfield | A Systematic Review and Meta-Analysis of the Brief Cognitive Assessment for Multiple Sclerosis (BICAMS)[END_REF].

Beyond the detection of cognitive disorders, this assessment is important for cognitive rehabilitation to evaluate speech progression in a therapeutic program. However, research on therapeutics in cognition is at a early stage, but preliminary work shows promise [START_REF] Sandroff | Will behavioral treatments for cognitive impairment in multiple sclerosis become standards-of-care?[END_REF]. Our approach could help detect patients who need rehabilation.

In our study, the EDSS score was 4 to 6.5 for PwMS, which corresponds to a moderate functional disability, and most patients were at an evolutionary stage of the disease.

Therefore, the PwMS included had risk of cognitive impairment, particularly executive impairments [START_REF] Huijbregts | Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS[END_REF], as suggested by impaired PwMS results as compared with controls on the SDMT. Our variables are relevant in this population with cognitive impairment. This method of evaluation could be studied in early MS or isolated clinical syndromes and taking into account potential confounding factors such as anxiety/depression and sleep disorders in addition to fatigue, type of MS, socio-professional status, and pharmacologic and nonpharmacologic treatments. Particular attention could be paid to the articulation, which was recently found associated with decline in information processing speed [START_REF] Friedova | Slowed articulation rate is associated with information processing speed decline in multiple sclerosis: A pilot study[END_REF]. Advances in data processessing and speech recognition could allow for use in clinical practice.

Limitations

We included 68 PwMS and 33 controls in this descriptive study. Although the number of participants needed was not calculated, the difference between the number of PwMS and controls gives rise to type 2 error, which could explain why the first inflection time of the curve tended to be similar between PwMS and controls. Moreover, the number of participants included did not allow us to analyse some subgroups such as MS type.

Among the potential confounding factors, dysarthria, education level, and depression were not examined. In most studies of VFT, dysarthria is not studied [START_REF] Vlaar | Verbal fluency assessment of patients with multiple sclerosis: test-retest and inter-observer reliability[END_REF][START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level][END_REF][START_REF] Crowe | Decrease in performance on the verbal fluency test as a function of time: evaluation in a young healthy sample[END_REF]. Future studies should include socio-professional level of patients. However, recently, Feenaughty et al. [START_REF] Feenaughty | Separate and Combined Influence of Cognitive Impairment and Dysarthria on Functional Communication in Multiple Sclerosis[END_REF] demonstrated a negative combined effect of dysarthria and cognitive impairment for communication function. Cardebat et al. [START_REF] Cardebat | Formal and semantic lexical evocation in normal subjects. Performance and dynamics of production as a function of sex, age and educational level][END_REF] showed the impact of education level during the VFT: performance was better in participants with a high educational level. Depression is common in PwMS [START_REF] Patten | Major depression in multiple sclerosis: a population-based perspective[END_REF], and it is also a symptom with a negative effect during the VFT [START_REF] Henry | A meta-analytic review of verbal fluency deficits in schizophrenia relative to other neurocognitive deficits[END_REF]. The FIS score was collected for all participants in our study and was greater for PwMS than controls. The impact of this psychosocial factor on cognitive function has been discussed [START_REF] Sandroff | Cardiorespiratory fitness and cognitive processing speed in multiple sclerosis: The possible roles of psychological symptoms[END_REF]. Future studies should take these factors affecting the performance of the VFT into account in to achieve the most objective results possible.

Conclusions

For PwMS, during the VFT, taking into account errors does not affect the variables studied depending on the time of word production. However, this should be analysed as an independent variable in a qualitative approach as a marker of inhibition disorders or working memory disorders. The use of these new variables allows for better characterizing cognitive disorders and a more accurate clinical interpretation of the results of the VFT for PwMS.

Further studies are needed, particularly to study the internal validity related to executive functions and communication on one hand and reproducibility of this method to use the variables in a therapeutic approach on the other hand.

Conflict of Interest.

We certify that this is an original work that has not been published nor submitted to another journal, that no party having a direct interest in the results of the research supporting this article has or will confer a benefit on us or on any organization with which we are associated, and that the French ethical committee approved this study.

Funding. This work was supported by the University Hospital of besançon. France.

Legends

Figure 1 .

 1 Figure 1. Word production curve illustrating variables used for verbal fluency analysis.

Figure 2 .

 2 Figure 2. A detailed example of words time production, in verbal fluency test (VFT), for a

Figure 1 :

 1 Figure 1:

Figure 2 :

 2 Figure 2:

Table 1 .

 1 Characteristics of persons with multiple sclerosis (PwMS) and controls. , body mass index; EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; SP, secondary progressive; PP, primary progressive; RR, relapsing remitting; FIS, fatigue impact scale; SDMT, Symbol Digit Modalities Test; NA, not applicable.

	PwMS (n = 68)	Controls (n = 33)	p-value

BMI* Non-parametric

Table 2 .

 2 Verbal fluency and comparison of the variables studied between PwMS and controls and between without and with errors conditions.

	PwMS (n = 68)	Controls (n = 33)	P value	P value
	No error With	No error With errors	PwMS vs	No error vs
			Controls	with errors

* Non-parametric test.


Keywords: E-commerce, online shopping, omnichannel retail, transport, mobility, environmental sustainability, conceptual framework

Internet, digitalisation and access to technology have transformed contemporary consumption patterns and habits. Whether or not these changes hold beneficial or detrimental implications for society is subject to ongoing debate. Specifically concerning the environmental impacts of online and omnichannel retail, claims have been made on both sides: crediting the efficiency of home deliveries versus individual shopping trips on the one hand and pointing out complex consumer behaviour on the other hand. Despite intensive research efforts, a solid consensus lacks. The disperse and contradicting scientific knowledge base that is currently available prevents policymakers and practitioners from implementing sustainability improving measures and from steering consumers towards sustainable practices. Supported by a systematic review of the literature, this article presents a framework for understanding the net environmental sustainability of shopping. The debate is broken down in three impact categories that need to be considered simultaneously: individual purchases, consumer behaviour and consumption geography. The majority of research articles focus on the environmental impact of purchasing a single item or a basket of items, in which in-store purchases are substituted by purchases online. Such studies conclude in favour of e-commerce. The balance shifts when taking changes in behaviour and geography into consideration. While behavioural reflections are on the rise, hardly any empirical work takes the spatial (re)organisation of businesses and consumers into account. The article surpasses the case-study approach and in doing so comprises the body of literature in a solid framework that is able to guide future discussions and research in more sustainable directions.

Introduction

Consumption patterns and habits have changed tremendously over the last decades, driven in particular by the development of the worldwide web, the digitalisation of processes throughout all aspects of society and the incremental improvements in access to technology. As with many societal developments, the consequences of transformed consumer behaviour are discussed and studied at large. Notable subjects of debate have been the impact of online shopping on local and independent retail, the implications of the on-demand economy on the organisation of work and the transformation of restaurants and supermarkets due to meal kit and prepared meal delivery services. Subject of ongoing debate as well is the impact of online and omnichannel retail on the environment, i.e. on climate change, air pollution, congestion and noise emissions. As a sector, retail is one of the most visible economic activities. Retailing accounts for 3.6 million businesses in Europe and, together with wholesaling, represents over 23% of all enterprises (European Commission, 2018). To organise their activities, retailers depend heavily on transport, a leading contributor to greenhouse gas and air polluting emissions [START_REF] Who | Health in the green economy: health co-benefits of climate change mitigationtransport sector[END_REF]. Transport operations of retailers involve different forms of transport; different sizes of containers and vehicles; and the scheduling and availability of drivers and vehicles [START_REF] Fernie | Logistics & retail management[END_REF]. Among consumers, travel for shopping represents approximately 20% of trips [START_REF] Guy | Sustainable transport choices' in consumer shopping: A review of the UK evidence[END_REF][START_REF] Jiao | Grocery Shopping How Individuals and Built Environments Influence Choice of Travel Mode[END_REF]. Transport for retail is an important aspect of mobility [START_REF] Hagberg | Travel modes in grocery shopping[END_REF] and thus vital to include in our global and local environmental sustainability goals. The advent of the online retail channel, said to replace many individual store visits by one efficient home delivery round, inevitably spurred questions about its capacity to lower the retail sector's environmental footprint [START_REF] Cairns | Delivering supermarket shopping: More or less traffic?[END_REF][START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF]. E-commerce is defined as the sale or purchase of goods or services, conducted over computer networks by methods specifically designed for the purpose of receiving or placing of orders, whereas payment and delivery of the goods or services do not have to be conducted online (OECD, 2011). In essence, the environmental sustainability question of shopping online or in-store is a matter of transport operations and conditions, albeit one that concerns retailers, logistics service providers as well as consumers. While e-commerce comprises pure players with an online-only approach, it also advanced omnichannel retail. This retail model comprehends the gradual change of pure players to a combined and integrated bricks-and-clicks approach [START_REF] Lazaris | From Multichannel to[END_REF][START_REF] Piotrowicz | Exploring Omnichannel Retailing -Common Expectations and Diverse Realities[END_REF][START_REF] Verhoef | From Multi-Channel Retailing to Omni-Channel Retailing[END_REF]. Traditional store-based retailers in particular transformed towards an omnichannel retail approach first (e.g. many high-street clothing chain brands). Later on, also established pure online players created a physical presence (e.g. Amazon with the acquisition of Whole Foods). As such, the retail sector developed into a realm in which online and offline channels blurred and converged into one another. Conventional in-store shopping has online extensions through mobile web-shops, kiosks and screens, among others. Contrary, through services such as click-and-collect (or buy-online-pick-up-in-store), ship-from-store and in-store return of online purchases, online shopping has a physical extension in-store. Along with these advancements, it has become increasingly difficult to understand the environmental implications of shopping in one retail channel over another. Accordingly, research initiatives aimed to provide an answer to this question are bound by parameters, assumptions and specific context conditions. Although based on solid scientific knowledge (e.g. consumers' average travel distances for shopping), these parameters, assumptions and conditions are often set quite strictly (e.g. specific product type), leading to contradicting research results. Setting system boundaries is necessary and not problematic in itself. In providing answers and guidelines on which way of shopping impacts the environment less, the narrow purchase-focused approach that is used, is. By comparing for example the vehicle-kilometres and vehicle emission factors associated with an in-store purchase and a purchase executed online, very detailed and context-specific research results are obtained that are hardly generalisable into actionable guidelines. More importantly, this approach disregards the broader behavioural and geographical developments that are pushed by e-commerce. On the behavioural side, [START_REF] Rosqvist | Online shopping habits and the potential for reductions in carbon dioxide emissions from passenger transport[END_REF] for example discuss "car-dependent lifestyles" facilitated by online shopping while Buldeo [START_REF] Buldeo Rai | How Does Consumers' Omnichannel Shopping Behaviour Translate into Travel and Transport Impacts? Case-Study of a Footwear Retailer in Belgium[END_REF] investigate the carbon footprint of pre and post-purchase travel behaviour. On the geographical side, [START_REF] Wygonik | Urban form and last-mile goods movement: Factors affecting vehicle miles travelled and emissions[END_REF] demonstrate the importance of land use conditions such as consumer density and warehouse location while [START_REF] Gee | Deliver Me from food waste: Model framework for comparing the energy use of meal-kit delivery and groceries[END_REF] consider supply chain differences in production and storage location for online and offline shopping scenarios. Possibly, such changes in consumer behaviour or consumption geography could impact the environmental footprint of online shopping to a more important extent.

The objective of this article is to comprehensively approach the environmental sustainability question of shopping online and offer a comprehensive view that explicitly includes behavioural and geographical considerations. By conducting a systematic review of the scientific literature, all relevant parameters are organised in a summary framework. The article contributes by providing a straightforward basis for discussion as well as communicable and actionable guidelines for every stakeholder involved in the retail realm, including consumers. The methodological approach applied in this article is presented in section two and its findings are discussed in section three. The fourth section ends with concluding remarks.

Methodology

Systematic literature review

The systematic literature review is a method of locating, appraising and synthesising evidence and an efficient technique for hypothesis testing, summarising the results of existing studies and assessing consistency among previous studies [START_REF] Petticrew | Systematic reviews from astronomy to zoology: myths and misconceptions[END_REF]. [START_REF] Petticrew | Systematic Reviews in the Social Sciences -A practical guide[END_REF] specifically point out their relevance to support policy and practice: by creating a valuable backdrop of evidence on which decisions about policies can draw and by providing a key source of evidence-based information to support and develop practice [START_REF] Petticrew | Systematic Reviews in the Social Sciences -A practical guide[END_REF]. In this way, the methodology fits the objective of this study seamlessly. Systematic literature reviews differ from traditional, narrative reviews in that they strive to locate all relevant studies and provide an explicit description of what types of studies are to be included [START_REF] Petticrew | Systematic reviews from astronomy to zoology: myths and misconceptions[END_REF]. In doing so, the method limits the impact of publication and selection bias on behalf of the reviewer. Systematic literature reviews usually start off with a clear question to be answered or hypothesis to be tested [START_REF] Petticrew | Systematic reviews from astronomy to zoology: myths and misconceptions[END_REF]. In this research, the methodology serves to firstly, verify and validate the understanding of the net environmental impact of online shopping that includes behavioural and geographical developments pushed by e-commerce and secondly, identify relevant parameters that need to be taken into consideration. Systematic literature reviews have been applied in research fields related to the subject of this study. For example, [START_REF] Seuring | Conducting content-analysis based literature reviews in supply chain management[END_REF] address their significance in supply chain management. The authors encourage researchers to "deliberately head for transparency and rigour in their review endeavours". [START_REF] Lagorio | Research in urban logistics: a systematic literature review[END_REF] consolidate the scientific knowledge on urban logistics published between 2000 and 2015. In doing so, the authors identify e-commerce as a recently emerged topic and call for "further methodological investigation". On the topic of e-commerce in particular, [START_REF] Mangiaracina | A review of the environmental implications of B2C e-commerce: a logistics perspective[END_REF] systematically review the environmental implications from a logistics perspective. The authors identify transport planning and management, (2) warehousing, (3) packaging and (4) distribution network design as key issues. Using three scientific databases (Science direct, Scopus and Google scholar) and 18 combinations of 23 keywords, a total of 43 articles was compiled on February 9 th , 2021. The keywords were selected to locate articles that empirically or theoretically compare (keyword "comparative") the environmental impact (keywords "environmental impact", "environmental sustainability", "carbon", "greenhouse gas", "CO2", "emissions") of shopping physical products online (keywords "e-commerce", "electronic commerce", "online retail", "online retailing", "electronic retail", "online shopping", "e-shopping", "home delivery", "omnichannel", "omni-channel") versus in-store (keywords "conventional", "traditional", "offline", "brick-and-mortar", "pickup", "pick-up"), to meet the article requirements. See annex 1 for a detailed overview. In addition, only peer-reviewed journal articles published after 2005 were included to guarantee quality and relevance, see annex 2 for a complete list. Only the 150 first results of Google scholar searches were taken into consideration. Despite an extensive list of references found in response to the keywords, only a comparatively limited number of articles actually compare online and offline shopping based on environmental variables such as carbon footprint, energy consumption or transportkilometres. Moreover, many of the same articles appeared in multiple searches. All articles were read, reviewed and analysed in a spreadsheet file. Two types of information were collected, first on the article details and content and second on the parameters applied in the articles. Specifically, information on the article title, year of publication and journal of publication was stored, as well as information on the geographical context to which the research applies, the product type investigated, whether the last mile or the broader supply chain was assessed and which impacts were investigated in the article. The latter categorisation addresses whether the research in the article focuses solely on the environmental impact associated with a purchase online or in-store, or if it also addresses behavioural and geographical changes by consumers, retailers or logistics service providers as a consequence of e-commerce.

Review corpus

The environmental impact of online shopping compared to shopping in-store is a relatively new research topic that emerged in the last twenty years, but gained particular momentum in the last decade. Less than half of the articles considered in this research were published between 2005 and 2015, more than half were published in the five years after. One fourth of articles (11) are set in the United States, one third (16) are focused on a European country and three articles investigate the Chinese case. This roughly reflects the places around the world were e-commerce developments are most mature, although countries such as Japan are missing and countries such as China are considerably underrepresented. In the aftermath of the COVID-19 pandemic, research on this topic is expected to continue to grow and its research contexts to diversify. Three types of journals were found to publish the articles considered in this research: ( 1 2) transport activities being key in assessing the environmental impact of ecommerce and (3) e-commerce being a rapidly growing supply chain type that disrupts logistics processes. Yet the absence of retailing journals is striking. Moreover, with endconsumers at the outset of supply chain demand (as buyers), as well as at the end (as receivers), also the lack of marketing and psychology journals stands out. It highlights the research needs associated with consumer behaviour. Geography journals are missing as well, hampering our understanding of how e-commerce shifts the spatial organisation of businesses (e.g. retailers and logistics service providers) and consumers and how that impacts on the environment. As such, this gap emphasizes the research needs associated with consumption geography.

Figure 1 illustrates the journals that contribute more than one article to the review corpus, the publication year of the articles and the investigated countries. This research focusses on shopping physical products, allowing to compare their environmental implications throughout conventional retail on the one hand and online retail on the other hand. Nevertheless, e-commerce has greatly facilitated the digitalised consumption of products that were once solely available in material form (e.g. entertainment such as music, books, films). Where these products required transport before, they do not anymore. An evolution that can be considered positive from the perspective of this research, although its behavioural consequences are even less investigated or understood. In our review corpus, most articles (24 articles) investigate nonfood products, mainly apparel, books, electronics and fast-moving consumer goods. Food products are studied as well (10 articles), mainly groceries but also meal kits. Meal kits have emerged as a research topic in the last years, comprising boxes of pre-portioned ingredients and corresponding recipes that are delivered directly to consumers as a way of replacing regular groceries [START_REF] Gee | Deliver Me from food waste: Model framework for comparing the energy use of meal-kit delivery and groceries[END_REF]. Six articles (or 14%) of the review corpus are literature reviews. Seven articles (or 16%) present questionnaire analyses and the majority (thirty articles or 70%) provide case-study calculations of environmental impacts. This article reorganises previously proposed concepts and considerations, extends them into a framework and proposes a straightforward basis to discuss and enhance the environmental sustainability of online shopping.

Findings

The findings of the systematic literature review can be fitted into the framework that has been proposed earlier. Thus, to understand the net environmental impact of online shopping, consideration needs to be taken of key parameters associated with (1) individual purchases in which deliveries are considered substitutes for store travel, (2) consumer behaviour transformed by e-commerce and (3) implications to consumption geography that transform the act of purchasing in a broader sense. All relevant parameters are presented in Figure 3 and Table 1, as well as discussed more profoundly in the following sections, focussing specifically on how they contribute to contradictions in research. Table 1. Three categories and their parameters to assess the net environmental impact of online shopping.

First level: individual purchases

Literature focuses primarily on what has been addressed in this article as "individual purchases", meaning that the calculated environmental impact of an in-store purchase is compared with the environmental impact of purchasing the same item online. To identify which way of shopping can be considered more environmentally sustainable, half (51% or 22 articles) of the reviewed articles employ this approach. Such research follows the so-called "substitution hypothesis", i.e. the assumption that online retail channels replace physical retail channels without any effects on individual or household travel patterns (Rotem-Mindali and Weltevreden, 2013). In doing so, [START_REF] Karbassi | Application of E-commerce in local home shopping and its consequences on energy consumption and air pollution reduction[END_REF] find 81.5% savings in fuel consumption by changing the shopping system from traditional shopping to eshopping.

This assumption might hold for stand-alone purchases such as books, as suggested by [START_REF] Borggren | Books from an environmental perspectivepart 1: Environmental impacts of paper books sold in traditional and internet bookshops[END_REF]. They conclude: "buying the book via an internet bookshop and getting it delivered resulted in the lowest potential global warming impact". This bias is also applied to research on groceries [START_REF] Figliozzi | Carbon emissions reductions in last mile and grocery deliveries utilizing air and ground autonomous vehicles[END_REF], fast-moving consumer goods [START_REF] Shahmohammadi | Comparative Greenhouse Gas Footprinting of Online versus Traditional Shopping for Fast-Moving Consumer Goods: A Stochastic Approach[END_REF] and meal kits, where it is more disputable. [START_REF] Heard | Comparison of life cycle environmental impacts from meal kits and grocery store meals[END_REF] state for example that meal kits "displace the typical grocery shopping experience for U.S. consumers, creating a systemic change", despite the fact that meal kits only supply dinner and still require to shop food and non-food items for other meals and activities. Building on substitution facilitates a more straightforward research design and allows to disregard more elusive, fickle and changeable behavioural parameters associated to shopping. As such, only included are so-called "first-order effects on travel patterns" or "direct transport impacts" [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF], on which detailed and accurate information is more likely to be available (e.g. from travel surveys, company data). Yet as research on this topic grows, behavioural impacts are increasingly taken into consideration.

The widely accepted premise of e-commerce being more environmentally sustainable than visiting stores, builds on the number of vehicle-kilometres per purchase. Transport distances are naturally lower in home delivery rounds as compared to individual store visits. [START_REF] Wygonik | Evaluating the Efficacy of Shared-use Vehicles for Reducing Greenhouse Gas Emissions: A U.S. Case Study of Grocery Delivery[END_REF] provide an illustration to this end, in which they describe home deliveries as "shared-use vehicle travel" (Figure 4). Because of the individual nature of their shopping trips, consumers are disadvantaged in terms of distance travelled for a single purchase [START_REF] Brown | Carbon emissions comparison of last mile delivery versus customer pickup[END_REF]). Yet the distance covered for delivery is influenced by so-called "stem distances": the travel required before the delivery round takes place, which largely depends on the shipping location (e.g. warehouse, store). Although not always taken into consideration, stores are replenished from warehouses too. Because of the international coverage of online retailing, as compared to the national or even regional presence of offline retailing based on stores, e-commerce warehouses are potentially located further. Partly because of these stem distances, [START_REF] Shahmohammadi | Comparative Greenhouse Gas Footprinting of Online versus Traditional Shopping for Fast-Moving Consumer Goods: A Stochastic Approach[END_REF] conclude that the environmental footprint of brick-and-mortar shopping in the United Kingdom is actually lower than shopping at a pure online retailer. 2010) calculate that a personal shopping trip by car emits twenty-four times more CO2 than a single drop within a home delivery round, while taking the bus lowers the difference to seven times the amount of CO2 emitted. Nonetheless, [START_REF] Hardi | Grocery Delivery or Customer Pickup -Influences on Energy Consumption and CO2 Emissions in Munich[END_REF] conclude that "even if a huge share of customers shifts to environmentally friendly modes for the shopping of groceries, a delivery would still offer opportunities to save energy and CO2". Ultimately, motorised road transport remains the main mode for personal and professional transport. Accordingly, vehicle types with a lower emission factor are preferred [START_REF] Hardi | Grocery Delivery or Customer Pickup -Influences on Energy Consumption and CO2 Emissions in Munich[END_REF]. [START_REF] Zhang | A Comparative Study of Environmental Impacts of Two Delivery Systems in the Business-to-Customer Book Retail Sector[END_REF] argue that the environmental impacts of trucks in the United States are much greater than those of vans in China. Vans are more common as well in a European context. Therefore, while [START_REF] Wygonik | Urban form and last-mile goods movement: Factors affecting vehicle miles travelled and emissions[END_REF] conclude that delivery services in a county in Washington, United States result in lower CO2 emissions but higher emission of air pollutants (i.e. NOx and PM10), this might not be the case when vans carry out deliveries. Most studies however focus on climate change implications, thereby omitting local impacts such as air pollution. Given the significant influence of vehicle type on environmental assessments, electrification is considered in several recent studies. [START_REF] Hardi | Grocery Delivery or Customer Pickup -Influences on Energy Consumption and CO2 Emissions in Munich[END_REF] find that using regular vans for grocery delivery leads to 73.3% in CO2 savings and 85.8% in savings when the vans are electric. [START_REF] Figliozzi | Carbon emissions reductions in last mile and grocery deliveries utilizing air and ground autonomous vehicles[END_REF] incorporates the growth of electric vehicles for personal transport and new autonomous vehicle types for goods transport: drones, sidewalk robots and road robots. He concludes that autonomous vehicles have a vast potential to reduce CO2 emissions when replacing regular vans and are even more efficient than electric vans. Even when substitution of individual purchases is assumed, several parameters in the framework are behavioural in nature. Connected to a particular purchase instead of purchase behaviour overall, they are discussed in this section. These parameters include purchase reception, i.e. whether a delivery at home was successful or failed and whether a purchase was retained or returned and purchase basket, i.e. whether a purchase contained one or multiple items. Typically, returns are higher when using online channels [START_REF] Wiese | Transport-related CO2 effects of online and brick-and-mortar shopping: A comparison and sensitivity analysis of clothing retailing[END_REF] and consumers are found to "over-order" knowing that they will send some of it back (e.g. clothing in several sizes and colours) [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF]. How delivery failures and purchase returns are treated by retailers and logistics service providers determines the degree of negativity it induces on the environment, but it also depends on consumers' travel behaviour [START_REF] Van Loon | A comparative analysis of carbon emissions from online retailing of fast moving consumer goods[END_REF].

On the logistics' side, delivery failures can be met with (multiple) redelivery attempts or the use of alternative delivery locations such as collection points and lockers. Some logistics service providers achieve very high first-time delivery rates as they leave deliveries with neighbours or in the garden [START_REF] Edwards | Comparative analysis of the carbon footprints of conventional and online retailing: A "last mile" perspective[END_REF]. Purchase returns can be consolidated into existing delivery rounds or collected on dedicated rounds. While the first is likely to generate very little additional distance, the second generates a lot more. [START_REF] Wiese | Transport-related CO2 effects of online and brick-and-mortar shopping: A comparison and sensitivity analysis of clothing retailing[END_REF] calculate that nearby brick-and-mortar retail is the more sustainable option when 10% of items is returned. The same is true for retailers at nineteen kilometers from consumers in case of 35% returns and at twenty-five kilometers when 100% of items are returned. Contrary, [START_REF] Schmitz | Critical analysis of carbon dioxide emissions in a comparison of ecommerce and traditional retail Research questions : What impact has the transportation flow before the last mile on the comparison of carbon dioxide emissions between traditional and onli[END_REF] finds that the return rate, even though it is three times higher for online shopping, does not significantly influence the end result in favour of online shopping.

On the consumers' side, redelivery can be requested and their collection and return trips to stores, collection points or neighbours can be carried out more sustainably or less. This is important to consider in discussing the environmental advantage of home delivery alternatives. Although they avoid delivery failure [START_REF] Pålsson | Energy consumption in e-commerce versus conventional trade channels -Insights into packaging, the last mile, unsold products and product returns[END_REF], they require consumers to carry out trips that can have a more negative environmental impact compared to home delivering a purchase twice. Despite its decisive impact, consumers' collection and return trips are often excluded in research [START_REF] Buldeo Rai | How Does Consumers' Omnichannel Shopping Behaviour Translate into Travel and Transport Impacts? Case-Study of a Footwear Retailer in Belgium[END_REF].

In terms of purchase basket, larger baskets are considered more efficient and thus sustainable as they are packaged and delivered together in one trip, as opposed to packing and delivering the very same number of items in separate trips [START_REF] Belavina | Online Grocery Retail: Revenue Models and Environmental Impact[END_REF]. Because they consider "the link between the retail channels and the basket size", Shahmohammadi et al. ( 2020) conclude that brick-and-mortar retail has a lower footprint than pure online retail but higher than brick-and-clicks, which carries out deliveries from stores. Yet in the study, the baskets considered for pure online retail (1, 2, 5) are much lower (5, 45, 100 for bricks-and-clicks and 1,30,70 for car-based brick-and-mortar). The size of a purchase basket also relates to the frequency of shopping and associated collection and delivery trips. For clothing, Hischier (2018) for example compares consumer profiles that go shopping very frequently and consumer profiles that only shop a few times a year. Thus, assuming that consumers need a certain number of items, the transport sustainability point of view prefers them to be bought in less shopping sessions rather than more. [START_REF] Van Loon | A comparative analysis of carbon emissions from online retailing of fast moving consumer goods[END_REF] summarise that "regardless of the fulfilment method, emissions per item increase inversely with basket size".

Particularly in e-commerce discussions, packaging is an important parameter to consider as it protects purchases during transport (i.e. thereby limiting damages, returns and redeliveries). Consumers use shopping bags for in-store shopping as well (although increasingly replaced by reusable bags) but comparatively more packaging is needed when purchases are not self-delivered by consumers to the home [START_REF] Mangiaracina | A review of the environmental implications of B2C e-commerce: a logistics perspective[END_REF]. [START_REF] Pålsson | Energy consumption in e-commerce versus conventional trade channels -Insights into packaging, the last mile, unsold products and product returns[END_REF] find that packaging consumes on average five times more energy per book in home delivery systems than in store supply chains. Beyond its protective purpose, packaging used for online purchases is often considered excessive and wasteful of material such as plastic, cardboard and paper. As such, [START_REF] Hischier | Car vs. Packaging-A First, Simple (Environmental) Sustainability Assessment of Our Changing Shopping Behaviour[END_REF] summarises the key question in assessing the environmental sustainability of shopping as follows: "car versus packaging". Consumers' car travel argues in favour of online shopping, while e-commerce packaging pleads in favour of shopping in-store. This trade-off is especially pressing for meal kits, in which each ingredient is wrapped separately in single-use packaging [START_REF] Gee | Deliver Me from food waste: Model framework for comparing the energy use of meal-kit delivery and groceries[END_REF]. In response to developments in reusable packaging, [START_REF] Matuštík | A comparative life cycle assessment of electronic retail of household products[END_REF] consider reusable plastic crates instead of cardboard boxes, demonstrating a great potential.

Second level: consumer behaviour

Eleven articles within the review corpus or 26% explicitly consider consumer behaviour and the ways in which it transformed due to e-commerce in their environmental comparisons of shopping. Echoing [START_REF] Matuštík | A comparative life cycle assessment of electronic retail of household products[END_REF], neither online shopping nor conventional retail significantly outcompete the other, it depends on consumer behaviour. Generally, research initiatives that address the "behavioural level" surpass the substitution bias and acknowledge the very different experiences that online shopping and in-store shopping offer. As such, they are not direct substitutes. This is important, as also [START_REF] Jaller | Evaluating the environmental impacts of online shopping: A behavioral and transportation approach[END_REF] note, as the assumption of full substitution exaggerates the potential of e-commerce to cut congestion and emissions, among others. Behavioural effects probably play out differently as well from one person, purchase and situation to the other [START_REF] Ren | The impact of geographic context on e-shopping behavior[END_REF]. Based on a survey in Germany, [START_REF] Frick | Everything is just a click away. Online shopping efficiency and consumption levels in three consumption domains[END_REF] demonstrate substitution effects for clothing but a direct consumption-increasing effects for digital devices. Although more detailed and generalisable data are difficult to get by [START_REF] Edwards | Comparative analysis of the carbon footprints of conventional and online retailing: A "last mile" perspective[END_REF], three hypotheses are proposed. [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF] describes modification, generation and addition effects that can occur when new technology interacts with old. In light of the e-commerce discussion, these terms entail the following:

• Modification occurs when online retail channels are used to conduct or change planned shopping activities, which is likely to reduce travel. • Generation occurs when online retail channels give new information, new acquaintances and new possibilities which induce more travel.

• Addition occurs when online retail channels come in addition to physical retail channels and there is no specific relationship between them. As such, not only direct transport effects are found important but also "indirect transport impacts", which includes changes in household and weekend travel, while "indirect nontransport impacts" result from changes in energy consumption elsewhere [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF]. Four parameters on consumer behaviour are proposed to evaluate the environmental impact of shopping. Online and omnichannel retail facilitates consumers to use and combine several retail channels for a single purchase [START_REF] Melacini | A Critical Comparison of Alternative Distribution Configurations in Omni-Channel Retailing in Terms of Cost and Greenhouse Gas Emissions[END_REF]. Different types of omnichannel purchase behaviour exist, with very different environmental effects [START_REF] Buldeo Rai | How Does Consumers' Omnichannel Shopping Behaviour Translate into Travel and Transport Impacts? Case-Study of a Footwear Retailer in Belgium[END_REF]. Shopping behaviour in which online browsing is combined with travel for purchasing (i.e. "webrooming"), collection (i.e. "click-and-collect") or delivery is not considered problematic as it does not result in additional transport. Possibly, it optimises shopping and its associated travel [START_REF] Wiese | Transport-related CO2 effects of online and brick-and-mortar shopping: A comparison and sensitivity analysis of clothing retailing[END_REF]. Promising from an efficiency point of view as well are "virtual stores", in which images of store shelves are attached in public spaces such as transport terminals that allow to scan items, create a virtual shopping cart and get the items home delivered [START_REF] Buldeo Rai | How Does Consumers' Omnichannel Shopping Behaviour Translate into Travel and Transport Impacts? Case-Study of a Footwear Retailer in Belgium[END_REF]. In these cases, modification effects seem likely. Other behaviours lead to more detrimental environmental effects as they induce several trips for a single purchase. Common examples include online purchases following an in-store visit (e.g. "showrooming" or ordering in-store selected items lower-priced online on a competitor web-shop) or home delivery of in-store purchases (i.e. "ship-from-store"). [START_REF] Edwards | Comparative analysis of the carbon footprints of conventional and online retailing: A "last mile" perspective[END_REF] assume that one in ten shopping trips results in no immediate purchase. A survey among shoppers highlighted by [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF] found that the third most purchased product type is "nothing" (16% of cases). Not only in-store browsing activities are considered, also shopping trips for social, recreational or hedonistic purposes are important to take into account [START_REF] Edwards | Comparative analysis of the carbon footprints of conventional and online retailing: A "last mile" perspective[END_REF]. Accordingly, a hypothetical shopping trip's negative environmental effects increase by a factor 1,1. On an individual level however, the environmental impact doubles with a second trip to the stores [START_REF] Edwards | Comparative analysis of the carbon footprints of conventional and online retailing: A "last mile" perspective[END_REF]. Yet as the use of technology among consumers and retailers has surged immensely, the share of shopping trips that are complemented by another trip is very likely to be higher. Although omnichannel retailers encourage the simultaneous and combined use of their channels to increase consumer convenience, loyalty and ultimately spending, a growing share of consumers behave omnichannel regardless. Ultimately, the omnichannel retail environment provides new information and possibilities to execute various purchase activities. As such, it is very likely to generate additional travel and negative environmental implications that are associated with travel.

When it comes to consumers' purchases overall, online and physical retail channels are not only used complementary to support one specific purchase, they also exist separately from each other. As flagged by [START_REF] Van Loon | A comparative analysis of carbon emissions from online retailing of fast moving consumer goods[END_REF], it is likely that shopping trips are still executed despite ordering certain products online. Consumers who frequently shop online are found to make the same number of trips to stores, as those who do not [START_REF] Shahmohammadi | Comparative Greenhouse Gas Footprinting of Online versus Traditional Shopping for Fast-Moving Consumer Goods: A Stochastic Approach[END_REF]. What's more, online grocery shoppers visit the supermarket even more frequent than traditional shoppers [START_REF] Van Loon | A comparative analysis of carbon emissions from online retailing of fast moving consumer goods[END_REF]. In this sense, ecommerce and the endless assortment it offers has become a preferred channel for specific and specialised purchases. Amplifying that trend is the surge of specialty web-shops for practically all types of products [START_REF] Kim | Designing and Assessing a Sustainable Networked Delivery (SND) System: Hybrid Business-to-Consumer Book Delivery Case Study[END_REF], as well as new services such as meal kit and prepared meal delivery [START_REF] Gee | Deliver Me from food waste: Model framework for comparing the energy use of meal-kit delivery and groceries[END_REF]. [START_REF] Edwards | Comparative analysis of the carbon footprints of conventional and online retailing: A "last mile" perspective[END_REF] find consumers making more frequent purchases of less items, often from several different companies and [START_REF] Bjørgen | E-groceries: Sustainable last mile distribution in city planning[END_REF] establish that consumers who order online groceries still visit physical stores to supplement online purchases. Compared to a pre e-commerce baseline situation, it seems only natural that a process of increasing fragmentation takes place. In essence, while any consolidation of shopping activities reduces their environmental impact, fragmented purchases create the opposite. Yet e-commerce does not only facilitate specific purchases from all over the globe, it also influences overall purchase demand. By creating new needs of products that were not available, known or even existent before or by offering products at lower prices, the worldwide web increases transport demand. Based on an activity diary dataset from Columbus metropolitan area in the United States, [START_REF] Ren | The impact of geographic context on e-shopping behavior[END_REF] conclude that "people who engage in more shopping activities in the physical world, are more likely to become e-shoppers". More recent studies, although based on surveys, follow this finding. "People who purchase online more frequently seem to have a higher shopping demand", say [START_REF] Shi | Does e-shopping replace shopping trips? Empirical evidence from Chengdu, China[END_REF] based on a survey in Chengdu, China. Similarly, a study in Germany points out that the time spent online is a considerable predictor for consumption overall [START_REF] Frick | Everything is just a click away. Online shopping efficiency and consumption levels in three consumption domains[END_REF]. The likelihood that active online shoppers reduce their shopping trips is thus potentially limited. Ultimately, even if online channels provide consumers with a more efficient and less timeconsuming alternative and full substitution takes place, the key question remains which activities fill up the saved time [START_REF] Laghaei | Impacts of home shopping on vehicle operations and greenhouse gas emissions: multi-year regional study[END_REF]. Addressing the question of overall activity demand, [START_REF] Rosqvist | Online shopping habits and the potential for reductions in carbon dioxide emissions from passenger transport[END_REF] highlight a rebound effect in trips for other purposes. When it comes to environmental sustainability, of interest is specifically which role transport plays therein: i.e. more unsustainable travel, more sustainable travel or no travel at all. For instance, the elimination of shopping trips can lead to other "maintenance trips" for eating meals, medical care, taking care of the household or personal obligations [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF]. Or think about going to the cinema or visiting a friend instead of performing a shopping trip, while food is delivered at home. True reductions in transport and negative environmental effects associated with it only occur if consumers stay at home or perform trips using other modes than private motorised ones. A reduction in consumer travel by car is essential if the environmental benefits of e-commerce are to be realised [START_REF] Van Loon | A comparative analysis of carbon emissions from online retailing of fast moving consumer goods[END_REF]. In that respect, Norwegian research by [START_REF] Bjørgen | E-groceries: Sustainable last mile distribution in city planning[END_REF] suggests that the use of home delivery services for food and groceries is associated with more environmentally friendly travel modes. Some consumers may use the internet to inform their conventional shopping decisions and rationalise their shopping-related travel, while others may continue to shop as much by conventional means as before. As such, while increasing the proportion of online shopping can improve drop densities and vehicle loading percentages, it still adds to traffic rather than replaces. Above all, what this shows is the need to take consumer behaviour into account from a comprehensive point of view: in its variation of activities taking place in various times and various places.

Third level: consumption geography Ultimately, the context in which any type of transport occurs determines its environmental impact. Beyond cultural preferences for certain transport modes or certain types of retail location, research refers to the importance of area density or whether consumers live in urban, sub-urban or rural settings. It reflects on transport distance, vehicle utilisation and transport mode parameters. "About half the variation in CO2 emissions can be explained by service area" conclude for example [START_REF] Wygonik | Evaluating the Efficacy of Shared-use Vehicles for Reducing Greenhouse Gas Emissions: A U.S. Case Study of Grocery Delivery[END_REF]. Ten articles or 23% of the review corpus consider wider geographical implications of e-commerce on environmental sustainability: seven articles (16%) do so next to assessing individual purchases, three articles (7%) while also taking consumer behaviour into account. They touch upon the spatial location and relocation of stores, warehouses and consumers, as well as the transport consequences that it entails. With consumers resorting more and more online for their purchases, a decline in the local store network is unavoidable and already set in motion in many cities, in particular the small to mid-sized ones [START_REF] Shi | Does e-shopping replace shopping trips? Empirical evidence from Chengdu, China[END_REF]. As store accessibility decreases, e-commerce is more likely to be adopted [START_REF] Ren | The impact of geographic context on e-shopping behavior[END_REF]. Of course, a future without stores is unlikely given the many reasons consumers still prefer the physical shopping experience, including the experience of "non-digital product attributes" (e.g. the feel of a shirt, the look of a pair of glasses), "instant gratification", advice and service from staff as well as social, recreational and hedonistic purposes. Also retailers' shift towards an omnichannel model, integrating online and physical channels, demonstrates the significance and importance of stores in consumers' contemporary shopping journeys. Yet, while urban inhabitants might remain well-serviced and able to reach their shops by foot, by bike or by public transport, the opposite might prove to be true for consumers living in suburban and rural areas. In accordance, [START_REF] Durand | Impacts of proximity deliveries on e-grocery trips[END_REF] find that clickand-collect locations near the heart of residential neighbourhoods leads changes in user behaviour, including the use of their car. Changes in location as they are anticipated now, are likely to have an impact on all other parameters considered in this research and thus on the environment. [START_REF] Rosqvist | Online shopping habits and the potential for reductions in carbon dioxide emissions from passenger transport[END_REF] support this statement: "the location of retailers can reduce CO2 emissions from customer travel by 22% while the location of shopping centres can lead to a reduction of 8-9%". The authors add that similar reductions of CO2 emissions are achieved by supporting neighbourhood stores and online shopping at the expense of shopping further away. A closely located store network is thus important for reducing the environmental impact in both online and physical shopping scenarios. Warehouse location (or distribution centre or logistics hub) equally matters [START_REF] Goodchild | An analytical model for vehicle miles traveled and carbon emissions for goods delivery scenarios[END_REF][START_REF] Wygonik | Urban form and last-mile goods movement: Factors affecting vehicle miles travelled and emissions[END_REF]. Two opposing trends are detected here, including the creation of centralised "XXL" warehouses ever further in the urban periphery and the reintroduction of smaller ("S" or "XS") warehouses on the edge of and in the middle of urban centres. [START_REF] Shahmohammadi | Comparative Greenhouse Gas Footprinting of Online versus Traditional Shopping for Fast-Moving Consumer Goods: A Stochastic Approach[END_REF] suggest retailers to locate warehouses closer to consumers in order to decrease stem distances and reduce their environmental footprints, [START_REF] Gee | Deliver Me from food waste: Model framework for comparing the energy use of meal-kit delivery and groceries[END_REF] raise a similar point for meal kit delivery. [START_REF] Kellner | Estimating the effect of changing retailing structures on the greenhouse gas performance of FMCG distribution networks[END_REF] find that a higher number of hubs and an improved concentration of retailers result in better greenhouse gas performance of the distribution system. Yet the closeness or remoteness of warehouses is evidently determined as well by consumers' choice of retailers. E-commerce facilitates consumers to shop at web-shops all over the world. For example, European consumers are particularly attracted by retailers from China and the United States, resulting in individually packaged products that are not rarely shipped by airfreight [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF]. In cases where air freight is used over traditional road transport, the impact of goods transport on the total energy consumption of e-commerce skyrockets, show [START_REF] Pålsson | Energy consumption in e-commerce versus conventional trade channels -Insights into packaging, the last mile, unsold products and product returns[END_REF]. Evidently, shopping online at local or remote retailers makes the world of a difference in terms of sustainability, although the difference between the two is rarely raised [START_REF] Mangiaracina | Assessing the environmental impact of logistics in online and offline B2C purchasing processes in the apparel industry[END_REF]. [START_REF] Schmitz | Critical analysis of carbon dioxide emissions in a comparison of ecommerce and traditional retail Research questions : What impact has the transportation flow before the last mile on the comparison of carbon dioxide emissions between traditional and onli[END_REF] urges for future research to shift its focus from the last mile to further up the transportation flow. What's more, e-commerce shipping charges never truly reflect the distance a purchase needs to cover, if a delivery price is charged at all. Ultimately, it is highly likely that e-commerce induced changes in behaviour impact consumers' mobility lifestyles in the long run. There are different scenarios possible, some with positive environmental effects and others that are more detrimental. A shift towards proximity shopping by foot or by bike in combination with online orders of items that cannot be found locally has the potential to render car-ownership obsolete. In this respect, [START_REF] Rosqvist | Online shopping habits and the potential for reductions in carbon dioxide emissions from passenger transport[END_REF] propose to use online shopping as a facilitator for implementing other policies promoting a less car-dependent planning regime. There are contrary views as well, in which e-commerce growth causes store closures in remote areas and as such forces consumers to rely on their cars even more [START_REF] Cullinane | From Bricks to Clicks: The Impact of Online Retailing on Transport and the Environment[END_REF].

Conclusions

In the aftermath of the COVID-19 pandemic, pushing an "e-commerce crash course" around the world, this research responds to an ever so relevant question: "what is the net environmental impact of online shopping?" With the emergence and continuous adoption of new retail models (e.g. omnichannel retail with click-and-collect and ship-from-store), new delivery services (e.g. meal kits and subscriptions) and digitalised consumption replacing physical products (e.g. music, books, films), it is increasingly difficult to understand the environmental implications of shopping in one retail channel over another. Universal models to outline how "the virtual" impacts "the physical" do not exist, instead this article proposes a framework of three impact categories that discusses (1) individual purchases, (2) consumer behaviour and (3) consumption geography. Evidently, there is no particular type of shopping that has an absolute environmental advantage and it is in no way possible to shop ourselves out of the environmental crisis. Yet it is clear that some developments and behaviours are more favourable than others. The framework lists fourteen parameters and the ways in which they positively or negatively affect the environment, as a way to guide necessary casestudy assessments in the future and support comprehensive understanding of the trade-offs that potentially take place. In the shopping sustainability question, many topics remain unexplored and provide ample avenues for future research. The most pressing gaps stretch further than the intensively researched last mile and instead concern behavioural consequences (including fragmented purchases and overall purchase demand) and spatial organisations of retail supply chains in their entirety (including store and warehouse locations), both transformed by and transforming online retail. The first need is to better comprehend consumer behaviour beyond generalising statistics of online shopping frequency, volume and spending. A clear view on the (different types of) e-consumer in relation to its general consumption patterns, travel habits and domestic circumstances is missing, which is ideally accumulated through standardised mapping of actual behaviour than highly specific questionnaires that limit comparability. The second need is to enhance our view on the supply chain operations of international online retailers, by mapping their retail and logistics footprint and the transport operations that are put in place. Focussing our research efforts on consumers with the heaviest purchase demand and similarly on retailers who contribute the most in supply, is perhaps the most promising way forward to accelerate environmental savings. Although consumer behaviour is scrutinised in particular, by detailing different ways in which e-commerce drives consumption and transport, it is vital to stress the shared responsibility of all stakeholders involved. When organised locally, efficiently and consciously, e-commerce has the potential to be a sustainable alternative to in-store shopping. Yet with increasingly convenient service conditions for delivery (e.g. instant) and return (e.g. collection at home), it is not set up to be. Consumer behaviour adapts accordingly while environmentally-conscious consumers are left with limited clarity and possibility to reduce their impact. In addressing the environmental implications that are directly associated with consumers' purchases, retailers and logistics service providers have important tools in hand to make significant positive contributions, such as greening their delivery fleet, reducing delivery failure, encouraging sustainable collection trips and transforming their packaging (in line with the individual purchase parameters). Together with policy-makers, they can create and raise awareness on a more conscious consumerism: which actions to take and decisions to avoid (in line with the consumer behaviour parameters) as well as plan for and implement optimal supply chains (in line with the consumption geography parameters). It is clear that e-commerce is here to stay regardless of environmental consequences. Although the margins of this systematic literature review are defined in the methodology, it is important to consider its limitations including biases based on publication, language and geography. Still, the framework attempts to encourage actions, behaviours and decisions that enhance the environmental footprint of online shopping processes and to guide a more comprehensive approach towards environmental e-commerce assessments in the future.

Figure 1 .

 1 Figure 1. Review corpus journals, publication year and country investigated.

Figure 2 .

 2 Figure 2. Product types in review corpus.

Figure 3 .

 3 Figure 3. Three categories to assess the net environmental impact of online shopping.

Figure 4 .

 4 Figure 4. Illustration of personal vehicle travel compared to shared-use vehicle travel by Wygonik and Goodchild (2012).

) environmental journals such as Environmental Science & Technology, Journal of Cleaner Production and Resources, Conservation & Recycling, (2) transport journals such as Research in Transportation Economics, Transport Reviews and Transportation Research and

	(3)
	logistics journals such as International Journal of Logistics Systems and Management,
	International Journal of Physical Distribution & Logistics Management and Supply Chain
	Forum: An International Journal. Evident explanations are (1) the focus on environmental
	issues, (

Author(s)

Article title Year Journal Karbassi, SM Tehrani, AR Everything is just a click away. Online shopping efficiency and consumption levels in three consumption domains