MS Cognitive Decline Linked To Brain Network Dysfunction

By Kate Johnson

Cognitive decline in patients with multiple sclerosis (MS) appears to be linked to the disruption of specific functional brain networks that can be seen on imaging, according to a new study from France and another from the Netherlands. However, along with this network disruption certain reorganization was also observed, suggesting patients may form new connections to preserve certain memory.

Discovery of this possible compensation mechanism could have important implications, senior author of the French study, Ismail Koubiyr, PhD, from INSERM, Bordeaux, France, and colleagues noted. However, “there is a debate in the current literature regarding the capacity of functional reorganization to compensate for structural damage and thus mitigate memory deficits,” he said in an interview.

In an article published May 19 in Frontiers in Neurology, the French authors speculated that “a future line of study would be to investigate how such functional reorganization can be stimulated in order to delay the appearance of cognitive impairment.”

Memory performance in early MS

The French study took 32 patients with early or suspected MS and followed them for 5 years, to examine the link between cognitive decline and functional brain changes on imaging. Ten healthy, matched controls were also included. The subjects went through a battery of neuropsychological tests at baseline, and again at 1 and 5 years. Special focus was placed on verbal and visuospatial memory, which were assessed with the Selective Reminding Test (SRT) and the Brief Visual Memory Test–Revised, respectively. Hippocampal volume was also measured along with various aspects of brain functional and structural connectivity.

The study found that hippocampal volume decreased significantly over time, and this corresponded with gradual verbal memory impairment measured through decreasing SRT scores, particularly the consistent long-term retrieval subitem of the SRT. The researchers also noted that this association was driven specifically by a decrease in left hippocampal volume.

However, the study also documented maintained visuospatial memory that was linked to a “progressive increase in connections between both hippocampi and the rest of the brain with preference for reinforcement of short distance connections.”

“Even though the hippocampus was altered – with progressive irreversible atrophy – from the onset of the disease, this structure was able to reinforce its short-distance functional connections to other regions of the brain,” Dr. Koubiyr said in an interview. “This functional reorganization was then associated with the maintenance of visuospatial memory.”

The authors noted this reorganization is “compatible with phenomena of compensation.”

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Image credit: Vecdog/DigitalVision Vectors/Getty Images

Conversion to cognitive impairment

The Dutch study also observed altered brain network connectivity that corresponded to declining cognition.

This study included 227 subjects from the Amsterdam Multiple Sclerosis cohort and followed them longitudinally for 5 years,

In all, 18.9% of the patients showed declines in cognition over the study period, with imaging evidence of disrupted connectivity shifting from the ventral attention network (VAN) to the default-mode network (DMN) as cognition worsened. “As the VAN normally relays information to the DMN, these results could indicate that in MS, normal processes crucial for maintaining overall network stability are progressively disrupted as patients clinically progress,” senior author Menno M. Schoonheim, PhD, from Vrije Universiteit Amsterdam, and colleagues noted.

Using a technique called eigenvector centrality mapping, the researchers also showed that the VAN increased its functional connectivity with both the DMN and the frontoparietal network among patients with impaired cognition. This corresponded with a decrease in visuo-spatial memory performance.

“It could be that the VAN is becoming more central to regulate other networks, but also that it is disrupting the functioning of other networks,” explained lead author Marijn Huiskamp, MSc, also from Vrije Universiteit Amsterdam, in an email. Since the increased VAN connectivity was related to a decrease in visuospatial memory performance, “our findings likely mean that the VAN increase is not beneficial for cognition. However, it could still be that this is compensatory and the VAN is trying to regulate other networks,” he said in an interview.

The researchers hope that further insight into the order in which various networks start to fail could lead to research into how to limit the dysfunction.

The French authors reported no conflicts of interest. Their study received funding from Teva Pharmaceuticals and Merck Serono and was further supported by the ARSEP Foundation, Bordeaux University Hospital, and Teva and Merck Serono. The work was further supported by public grants from the French Agence Nationale de la Recherche. The Dutch authors reported numerous disclosures with various sources in industry.

Cognitive rehabilitation in MS

By Terry Lee-Wilk, PhD, and John DeLuca, PhD


Cognitive impairment is common in persons with multiple sclerosis (PwMS), with up to 65% experiencing symptoms.1 Cognitive symptoms can emerge early in the disease course, persist over time, and occur in all subtypes of MS. Studies examining mechanisms of dysfunction in MS have traditionally focused on lesion burden and location. However, there is burgeoning evidence that the functional connections between structural brain regions may also play a critical role.2,3 Cognitive impairment has adverse consequences for important aspects of daily functioning, including occupational status, social function, and quality of life.4 While disease-modifying treatments (DMTs) are known to help reduce relapses associated with MS, there is little evidence that they are helpful in improving cognition.

However, there is a growing evidence base for nonpharmacological approaches to treating cognitive dysfunction. Cognitive rehabilitation consists of systematic, functionally oriented therapeutic activities intended to achieve change, reduce cognitive symptoms, and improve the well-being of the patient. The first step in developing a cognitive rehabilitation plan is to assess an individual’s neurocognitive strengths, weaknesses, and areas of impairment.5,6 Cognitive rehabilitation interventions can assist individuals in two ways – via restoration of specific cognitive abilities and/or through development of compensatory strategies to mitigate cognitive dysfunction. In addition, other nonpharmacologic approaches, such as different forms of physical exercise, have shown promising data in benefiting cognitive function through neural reorganization and compensation in PwMS.7

Over the last 10-15 years, there has been a proliferation of studies examining interventions to address cognitive symptoms in MS. Although variability in research methodology and quality has limited the conclusions that can be drawn from select studies, there are approaches that have garnered significant empirical support. A recent review of the scientific literature on cognitive rehabilitation in MS found that certain studies exhibited high-quality (class I) ratings regarding rigorous design and research methodology.8 One example, the modified Story Memory Technique (mSMT) is a cognitive rehabilitation program with a strong enough evidence base to be recommended as a practice standard for PwMS. The mSMT is a 10-session intervention that involves the use of cognitive strategies to improve verbal learning and memory. This intervention has shown efficacy across multiple studies and has also been associated with increased activity in brain regions involved in learning and memory.9 Other programs have shown preliminary efficacy, but ongoing research is warranted.10 While a solid foundation has emerged regarding the benefits of cognitive rehabilitation for PwMS, more high-quality studies are needed to explore the ecological validity and generalizability of these interventions in the real world.

In summary, early application of nonpharmacologic approaches in the treatment of cognitive dysfunction in MS is warranted. These interventions are empirically supported, low cost, and low risk, and should be included as part of comprehensive care for PwMS. Given that cognitive symptoms in MS can vary widely across individuals, it is important for treatments to be person-centered, evidence-based, and feasible. The treatment plan should ideally be designed in accordance with the individual’s cognitive strengths, weaknesses, and personal goals, while taking sociocultural and demographic factors into account. Personality characteristics may inform whether individual or group modalities is most fitting and practical considerations may impact the decision to use face-to-face versus telehealth platforms. While more research is needed, clinicians are encouraged to consider recommending cognitive rehabilitation programs as a first line treatment approach for MS-associated cognitive dysfunction.

Dr. Lee-Wilk is a program manager of neuropsychology, associate director of neuropsychology, MS Center of Excellence – East, Veterans Affairs Maryland Health Care System, and an adjunct assistant professor, department of neurology, University of Maryland, Baltimore. Dr. DeLuca is senior vice president for research at Kessler Foundation in West Orange, N.J.


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3. Boscheron J et al. Front Neurol. 2021 May 19. doi: 10.3389/fneur.2021.667531.

4. Benedict RH et al. J Neurol Sci. 2005 Apr 15. doi: 10.1016/j.jns.2004.12.009.

5. Kalb R et al. Mult Scler. 2018 Nov;24(13):1665-80. doi: 10.1177/1352458518803785.

6. Deluca J et al. Nat Rev Neurol. 2020;16(6):319-32.

7. Gharakhanlou R et al. Mult Scler. 2020 May 11. doi: 10.1177/1352458520917935.

8. Goverover Y et al. Arch Phys Med Rehabil. 2018 Feb;99(2):390-407. doi: 10.1016/j.apmr.2017.07.021.

9. Leavitt VM et al. Brain Imaging Behav. 2014 Sep;8(3):394-402. doi: 10.1007/s11682-012-9183-2.

10. Chen MH et al. J Neurol. 2021 May 24. doi: 10.1007/s00415-021-10618-2.