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Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. Objectives: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. Method: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington’s Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. Results: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. Conclusions: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.
Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder. The striatum is one of the first brain regions that show detectable atrophy in HD. Previous studies using functional magnetic resonance imaging (fMRI) at 3 tesla (3 T) revealed reduced functional connectivity between striatum and motor cortex in the prodromal period of HD. Neuroanatomical and neurophysiological studies have suggested segregated corticostriatal pathways with distinct loops involving different cortical regions, which may be investigated using fMRI at an ultra-high field (7 T) with enhanced sensitivity compared to lower fields. Objectives: We performed fMRI at 7 T to assess functional connectivity between the striatum and several chosen cortical areas including the motor and prefrontal cortex, in order to better understand brain changes in the striatum-cortical pathways. Method: 13 manifest subjects (age 51 ± 13 years, cytosine-adenine-guanine [CAG] repeat 45 ± 5, Unified Huntington’s Disease Rating Scale [UHDRS] motor score 32 ± 17), 8 subjects in the close-to-onset premanifest period (age 38 ± 10 years, CAG repeat 44 ± 2, UHDRS motor score 8 ± 2), 11 subjects in the far-from-onset premanifest period (age 38 ± 11 years, CAG repeat 42 ± 2, UHDRS motor score 1 ± 2), and 16 healthy controls (age 44 ± 15 years) were studied. The functional connectivity between the striatum and several cortical areas was measured by resting state fMRI at 7 T and analyzed in all participants. Results: Compared to controls, functional connectivity between striatum and premotor area, supplementary motor area, inferior frontal as well as middle frontal regions was altered in HD (all p values <0.001). Specifically, decreased striatum-motor connectivity but increased striatum-prefrontal connectivity were found in premanifest HD subjects. Altered functional connectivity correlated consistently with genetic burden, but not with clinical scores. Conclusions: Differential changes in functional connectivity of striatum-prefrontal and striatum-motor circuits can be found in early and premanifest HD. This may imply a compensatory mechanism, where additional cortical regions are recruited to subserve functions that have been impaired due to HD pathology. Our results suggest the potential value of functional connectivity as a marker for future clinical trials in HD.
Background and Objective: Transcranial random noise stimulation (tRNS) is an emerging non-invasive brain stimulation technique to modulate brain function, with previous studies highlighting its considerable benefits in therapeutic stimulation of the motor system. However, high variability of results and bidirectional task-dependent effects limit more widespread clinical application. Task dependency largely results from a lack of understanding of the interaction between externally applied tRNS and the endogenous state of neural activity during stimulation. Hence, the aim of this study was to investigate the task dependency of tRNS-induced neuromodulation in the motor system using a finger-tapping task (FT) versus a go/no-go task (GNG). We hypothesized that the tasks would modulate tRNS’ effects on corticospinal excitability (CSE) and task performance in opposite directions.
Methods: Thirty healthy subjects received 10 min of tRNS of the dominant primary motor cortex in a double-blind, sham-controlled study design. tRNS was applied during two well-established tasks tied to diverging brain states. Accordingly, participants were randomly assigned to two equally-sized groups: the first group performed a simple motor training task (FT task), known primarily to increase CSE, while the second group performed an inhibitory control task (go/no-go task) associated with inhibition of CSE. To establish task-dependent effects of tRNS, CSE was evaluated prior to- and after stimulation with navigated transcranial magnetic stimulation.
Results: In an ‘activating’ motor task, tRNS during FT significantly facilitated CSE. FT task performance improvements, shown by training-related reductions in intertap intervals and increased number of finger taps, were similar for both tRNS and sham stimulation. In an ‘inhibitory’ motor task, tRNS during GNG left CSE unchanged while inhibitory control was enhanced as shown by slowed reaction times and enhanced task accuracy during and after stimulation.
Conclusion: We provide evidence that tRNS-induced neuromodulatory effects are task-dependent and that resulting enhancements are specific to the underlying task-dependent brain state. While mechanisms underlying this effect require further investigation, these findings highlight the potential of tRNS in enhancing task-dependent brain states to modulate human behavior.
Changes in Interhemispheric Motor Connectivity Across the Lifespan: A Combined TMS and DTI Study
(2019)
Age-related decline in interhemispheric connectivity between motor areas has been reported with both transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) measurements. However, not all studies were able to confirm these findings, and previous studies did not apply structural (DTI) and functional (TMS) measurements within each individual appropriately. Here, we investigated age dependency of the ipsilateral silent period (ISP) and integrity of fibers in the corpus callosum as operationalized by fractional anisotrophy (FA), using TMS and DTI, respectively, in 20 participants between 19 and 72 years of age. We found age-dependent increase for ISP, and decrease of FA, both indicating a decrease in interhemispheric inhibition, with a negative association between FA and ISP for the dominant hemisphere (r = −0.39, p = 0.043). Our findings suggest that aging leads to decline of interhemispheric motor connectivity, as evidenced in both structural and functional parameters, which should be taken into account when interpreting disease- or medication-related changes.
Background: Intensive speech-language therapy (SLT) can promote recovery from chronic post-stroke aphasia, a major consequence of stroke. However, effect sizes of intensive SLT are moderate, potentially reflecting a physiological limit of training-induced progress. Transcranial direct current stimulation (tDCS) is an easy-to-use, well-tolerated and low-cost approach that may enhance effectiveness of intensive SLT. In a recent phase-II randomized controlled trial, 26 individuals with chronic post-stroke aphasia received intensive SLT combined with anodal-tDCS of the left primary motor cortex (M1), resulting in improved naming and proxy-rated communication ability, with medium-to-large effect sizes.
Aims: The proposed protocol seeks to establish the incremental benefit from anodal-tDCS of M1 in a phase-III randomized controlled trial with adequate power, ecologically valid outcomes, and evidence-based SLT.
Methods: The planned study is a prospective randomized placebo-controlled (using sham-tDCS), parallel-group, double-blind, multi-center, phase-III superiority trial. A sample of 130 individuals with aphasia at least 6 months post-stroke will be recruited in more than 18 in- and outpatient rehabilitation centers.
Outcomes: The primary outcome focuses on communication ability in chronic post-stroke aphasia, as revealed by changes on the Amsterdam-Nijmegen Everyday Language Test (A-scale; primary endpoint: 6-month follow-up; secondary endpoints: immediately after treatment, and 12-month follow-up). Secondary outcomes include measures assessing linguistic-executive skills, attention, memory, emotional well-being, quality of life, health economic costs, and adverse events (endpoints: 6-month follow-up, immediately after treatment, and 12-month follow-up).
Discussion: Positive results will increase the quality of life for persons with aphasia and their families while reducing societal costs. After trial completion, a workshop with relevant stakeholders will ensure transfer into best-practice guidelines and successful integration within clinical routine.
Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03930121.
Im Rahmen der vorliegenden Arbeit wurde bei 41 Patienten mit JME das EFHC1-Gen sequenziert und die identifizierten Varianten mit in mehreren vorherigen Studien beschriebenen Prädiktoren für das klinische Outcome korreliert. Insgesamt konnten drei Varianten - p.Phe229Leu, p.Arg182His und p.Arg294His - identifiziert werden.
Die Variante p.Phe229Leu, welche bei zwei Patienten auftrat, konnte mit einem milderen JME Subtyp assoziiert werden. Drei Patienten wiesen die Variante p.Arg182His auf und zeigten eine erhöhte Neigung zur Ausbildung einer photoparoxysmalen Reaktion. Eine Assoziation mit einem frühen Auftreten der Epilepsie (≤10. Lebensjahr) und einem Subtyp der JME, die sich aus einer kindlichen Absencenepilepsie entwickelt, konnte bei den zwei Patienten mit Variante p.Arg294His nachgewiesen werden, aufgrund der geringen Zahl an untersuchten Patienten jedoch ohne statistische Relevanz. In Zukunft könnte möglicherweise das Vorliegen einer dieser Varianten für klinische Fragestellungen hilfreich sein, um im Zusammenspiel mit klinischen Parametern eine Aussage über den Langzeitverlauf der JME und damit verbundene Therapieentscheidungen treffen zu können.
Nach aktuellen Bewertungen in der Human Gene Mutation Database sind p.Arg182His und p.Arg294His als benigne Varianten/Polymorphismen und die Variante p.Phe229Leu als wahrscheinlich pathogene Variante einzustufen. Somit muss eingeschätzt werden, dass die Varianten eher einen modifizierenden Einfluss auf den Krankheitsverlauf nehmen und nicht ursächlich für die JME sind.
Zusammenfassend sprechen die Ergebnisse dafür, dass es sich bei der JME um ein heterogenes Krankheitsbild handelt. Vorrangiges Ziel zukünftiger Studien sollte sein, weitere potenzielle Kandidatengene zu identifizieren und zu untersuchen.