Matthew P. Kirschen

Load- and practice-dependent increases in cerebro-cerebellar activation in verbal working memory: an fMRI study

Load-dependent and practice-related changes in neocortical and cerebellar structures involved in verbal working memory (VWM) were investigated using functional MRI (fMRI) and a two alternative forced choice Sternberg paradigm. Using working memory loads ranging from 2 to 6 letters, regions exhibiting linear and quadratic trends in load-dependent activations were identified. Behaviorally, reaction time measurements revealed significant linear increases with increasing memory load, and significant decreases with increased task practice. Brain activations indicated a preponderance of linear load-dependent responses in both superior (lobule VI/Crus I) and inferior (lobule VIIB/VIIIA) cerebellar hemispheres, as well as in areas of neocortex including left precentral (BA 6), inferior frontal (BA 47), parahippocampal (BA 35), inferior parietal (BA 40), cingulate (BA 32), and right inferior and middle frontal (BA 46/47) regions. Fewer voxels exhibited quadratic without linear trends with the most prominent of these activations located in left inferior parietal (BA 40), precuneus, and parahippocampal regions. Analysis of load x session interactions revealed that right inferior cerebellar and left inferior parietal activations increased with practice, as did the correlations between activation in each region with reaction time, suggesting that changes in this cerebro-cerebellar network underlie practice-related increases in efficiency of VWM performance. These results replicate and extend our previous findings of fMRI activation in the cerebellum during VWM, and demonstrate predominately linear increases in cerebro-cerebellar activation with increasing memory load as well as changes in network function with increased task proficiency.

Discovery and Disclosure of Incidental Findings in Neuroimaging Research

To examine different protocols for handling incidental findings on brain research MRIs, and provide a platform for establishing formal discussions of related ethical and policy issues.

Practical approaches to incidental findings in brain imaging research.

A decade of empirical work in brain imaging, genomics, and other areas of research has yielded new knowledge about the frequency of incidental findings, investigator responsibility, and risks and benefits of disclosure. Straightforward guidance for handling such findings of possible clinical significance, however, has been elusive. In early work focusing on imaging studies of the brain, we suggested that investigators and institutional review boards must anticipate and articulate plans for handling incidental findings. Here we provide a detailed analysis of different approaches to the problem and evaluate their merits in the context of the goals and setting of the research and the involvement of neurologists, radiologists, and other physicians. Protecting subject welfare and privacy, as well as ensuring scientific integrity, are the highest priorities in making choices about how to handle incidental findings. Forethought and clarity will enable these goals without overburdening research conducted within or outside the medical setting.

Modality specific cerebro-cerebellar activations in verbal working memory: An fMRI study

Verbal working memory (VWM) engages frontal and temporal/parietal circuits subserving the phonological loop, as well as, superior and inferior cerebellar regions which have projections from these neocortical areas. Different cerebro-cerebellar circuits may be engaged for integrating aurally- and visually-presented information for VWM. The present fMRI study investigated load (2, 4, or 6 letters) and modality (auditory and visual) dependent cerebro-cerebellar VWM activation using a Sternberg task. FMRI revealed modality-independent activations in left frontal (BA 6/9/44), insular, cingulate (BA 32), and bilateral inferior parietal/supramarginal (BA 40) regions, as well as in bilateral superior (HVI) and right inferior (HVIII) cerebellar regions. Visual presentation evoked prominent activations in right superior (HVI/CrusI) cerebellum, bilateral occipital (BA19) and left parietal (BA7/40) cortex while auditory presentation showed robust activations predominately in bilateral temporal regions (BA21/22). In the cerebellum, we noted a visual to auditory emphasis of function progressing from superior to inferior and from lateral to medial regions. These results extend our previous findings of fMRI activation in cerebro-cerebellar networks during VWM, and demonstrate both modality dependent commonalities and differences in activations with increasing memory load.

Verbal Memory Impairments in Children after Cerebellar Tumor Resection

This study was designed to investigate cerebellar lobular contributions to specific cognitive deficits observed after cerebellar tumor resection. Verbal working memory (VWM) tasks were administered to children following surgical resection of cerebellar pilocytic astrocytomas and age-matched controls. Anatomical MRI scans were used to quantify the extent of cerebellar lobular damage from each patients resection. Patients exhibited significantly reduced digit span for auditory but not visual stimuli, relative to controls, and damage to left hemispheral lobule VIII was significantly correlated with this deficit. Patients also showed reduced effects of articulatory suppression and this was correlated with damage to the vermis and hemispheral lobule IV/V bilaterally. Phonological similarity and recency effects did not differ overall between patients and controls, but outlier patients with abnormal phonological similarity effects to either auditory or visual stimuli were found to have damage to hemispheral lobule VIII/VIIB on the left and right, respectively. We postulate that damage to left hemispheral lobule VIII may interfere with encoding of auditory stimuli into the phonological store. These data corroborate neuroimaging studies showing focal cerebellar activation during VWM paradigms, and thereby allow us to predict with greater accuracy which specific neurocognitive processes will be affected by a cerebellar tumor resection.

Enhancement of phonological memory following Transcranial Magnetic Stimulation (TMS)

Phonologically similar items (mell, rell, gell) are more difficult to remember than dissimilar items (shen, floy, stap), likely because of mutual interference of the items in the phonological store. Low-frequency transcranial magnetic stimulation (TMS), guided by functional magnetic resonance imaging (fMRI) was used to disrupt this phonological confusion by stimulation of the left inferior parietal (LIP) lobule. Subjects received TMS or placebo stimulation while remembering sets of phonologically similar or dissimilar pseudo-words. Consistent with behavioral performance of patients with neurological damage, memory for phonologically similar, but not dissimilar, items was enhanced following TMS relative to placebo stimulation. Stimulation of a control region of the brain did not produce any changes in memory performance. These results provide new insights into how the brain processes verbal information by establishing the necessity of the inferior parietal region for optimal phonological storage. A mechanism is proposed for how TMS reduces phonological confusion and leads to facilitation of phonological memory.

Sports-Related Concussion Testing

Due to the recent focus on concussion in sports, a number of tests have been developed to diagnose and manage concussion. While each test measures different brain functions, no single test has been shown to quickly and reliably assess concussion in all cases. In addition, most of the current concussion tests have not been validated by scientific investigation. This review identifies the pros and cons of the most commonly used noninvasive tests for concussion in order to provide a more complete picture of the resources that are available for concussion testing. The potential utility of research tools such as the head impact telemetry system, advanced magnetic resonance imaging protocols, and biomarkers are discussed in the context of the currently employed tools.

Legal and ethical implications in the evaluation and management of sports-related concussion

Objective: To examine the ethical and legal issues physicians face when evaluating and managing athletes with sports-related concussions, and to offer guidance to physicians as they navigate these situations. Results: This position paper reviews and compares the components of sports-related concussion laws, including education, removal from play, and clearance for return to play. It highlights the challenges privacy laws present relevant to providing care to concussed athletes and suggests ways to help physicians overcome these obstacles. The report also explores the ethical considerations physicians should bear in mind as they evaluate and manage concussed athletes, addressing them through a framework that includes considerations of professionalism, informed decision-making, patient autonomy, beneficence, nonmaleficence, conflicts of interest, and distributive justice. Conclusions: Physicians caring for concussed athletes have an ethical obligation to ensure that their primary responsibility is to safeguard the current and future physical and mental health of their patients. Physicians have a duty to provide athletes and their parents with information about concussion risk factors, symptoms, and the risks for postconcussion neurologic impairments. Physicians should facilitate informed and shared decision-making among athletes, parents, and medical teams while protecting athletes from potential harm. Additionally, including concussion evaluation and management training in neurology residency programs, as well as developing a national concussion registry, will benefit patients by the development of policies and clinical guidelines that optimize prevention and treatment of concussive head injury.

Concurrent Validity and Reliability of Retrospective Scoring of the Pediatric National Institutes of Health Stroke Scale

Background and Purpose— The Pediatric National Institutes of Health Stroke Scale (PedNIHSS), an adaptation of the adult National Institutes of Health Stroke Scale, is a quantitative measure of stroke severity shown to be reliable when scored prospectively. The ability to calculate the PedNIHSS score retrospectively would be invaluable in the conduct of observational pediatric stroke studies. The study objective was to assess the concurrent validity and reliability of estimating the PedNIHSS score retrospectively from medical records. Methods— Neurological examinations from medical records of 75 children enrolled in a prospective PedNIHSS validation study were photocopied. Four neurologists of varying training levels blinded to the prospective PedNIHSS scores reviewed the records and retrospectively assigned PedNIHSS scores. Retrospective scores were compared among raters and to the prospective scores. Results— Total retrospective PedNIHSS scores correlated highly with total prospective scores (R2=0.76). Interrater reliability for the total scores was “excellent” (intraclass correlation coefficient, 0.95; 95% CI, 0.94–0.97). Interrater reliability for individual test items was “substantial” or “excellent” for 14 of 15 items. Conclusions— The PedNIHSS score can be scored retrospectively from medical records with a high degree of concurrent validity and reliability. This tool can be used to improve the quality of retrospective pediatric stroke studies.

An Ethics Perspective on Transcranial Magnetic Stimulation (TMS) and Human Neuromodulation

This paper concerns the ethics of human neuromodulation using transcranial magnetic stimulation (TMS). We examine the challenges of modulating the brain with TMS through the research ethics lens and in clinical medicine for treating frank pathology, primarily in psychiatric diseases. We also consider contemporary issues raised in the neuroethics literature about managing unexpected findings, and relate these to TMS and to other frontier neurotechnology that is becoming openly available in the public domain. We argue that safety and informed consent are of paramount importance for TMS, but that personal values and sociocultural factors must also be considered when examining the promise of this technology and applications that ought to be highlighted for extra precautions.