Fatemeh Geranmayeh

Cognitive control and its impact on recovery from aphasic stroke

Aphasic deficits are usually only interpreted in terms of domain-specific language processes. However, effective human communication and tests that probe this complex cognitive skill are also dependent on domain-general processes. In the clinical context, it is a pragmatic observation that impaired attention and executive functions interfere with the rehabilitation of aphasia. One system that is important in cognitive control is the salience network, which includes dorsal anterior cingulate cortex and adjacent cortex in the superior frontal gyrus (midline frontal cortex). This functional imaging study assessed domain-general activity in the midline frontal cortex, which was remote from the infarct, in relation to performance on a standard test of spoken language in 16 chronic aphasic patients both before and after a rehabilitation programme. During scanning, participants heard simple sentences, with each listening trial followed immediately by a trial in which they repeated back the previous sentence. Listening to sentences in the context of a listen–repeat task was expected to activate regions involved in both language-specific processes (speech perception and comprehension, verbal working memory and pre-articulatory rehearsal) and a number of task-specific processes (including attention to utterances and attempts to overcome pre-response conflict and decision uncertainty during impaired speech perception). To visualize the same system in healthy participants, sentences were presented to them as three-channel noise-vocoded speech, thereby impairing speech perception and assessing whether this evokes domain general cognitive systems. As expected, contrasting the more difficult task of perceiving and preparing to repeat noise-vocoded speech with the same task on clear speech demonstrated increased activity in the midline frontal cortex in the healthy participants. The same region was activated in the aphasic patients as they listened to standard (undistorted) sentences. Using a region of interest defined from the data on the healthy participants, data from the midline frontal cortex was obtained from the patients. Across the group and across different scanning sessions, activity correlated significantly with the patients’ communicative abilities. This correlation was not influenced by the sizes of the lesion or the patients’ chronological ages. This is the first study that has directly correlated activity in a domain general system, specifically the salience network, with residual language performance in post-stroke aphasia. It provides direct evidence in support of the clinical intuition that domain-general cognitive control is an essential factor contributing to the potential for recovery from aphasic stroke.

Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.

Task-induced brain activity in aphasic stroke patients: what is driving recovery?

Based on the interpretation and reinterpretation of published functional neuroimaging and clinical neuropsychological data, Geranmayeh et al. argue that recovery from aphasic stroke may be due as much to the function of high-order, domain-general networks as to recovery of language-specific networks. This distinction has implications for rehabilitation.

Overlapping Networks Engaged during Spoken Language Production and Its Cognitive Control

Spoken language production is a complex brain function that relies on large-scale networks. These include domain-specific networks that mediate language-specific processes, as well as domain-general networks mediating top-down and bottom-up attentional control. Language control is thought to involve a left-lateralized fronto-temporal-parietal (FTP) system. However, these regions do not always activate for language tasks and similar regions have been implicated in nonlinguistic cognitive processes. These inconsistent findings suggest that either the left FTP is involved in multidomain cognitive control or that there are multiple spatially overlapping FTP systems. We present evidence from an fMRI study using multivariate analysis to identify spatiotemporal networks involved in spoken language production in humans. We compared spoken language production (Speech) with multiple baselines, counting (Count), nonverbal decision (Decision), and “rest,” to pull apart the multiple partially overlapping networks that are involved in speech production. A left-lateralized FTP network was activated during Speech and deactivated during Count and nonverbal Decision trials, implicating it in cognitive control specific to sentential spoken language production. A mirror right-lateralized FTP network was activated in the Count and Decision trials, but not Speech. Importantly, a second overlapping left FTP network showed relative deactivation in Speech. These three networks, with distinct time courses, overlapped in the left parietal lobe. Contrary to the standard model of the left FTP as being dominant for speech, we revealed a more complex pattern within the left FTP, including at least two left FTP networks with competing functional roles, only one of which was activated in speech production.

The contribution of the inferior parietal cortex to spoken language production

This functional MRI study investigated the involvement of the left inferior parietal cortex (IPC) in spoken language production (Speech). Its role has been apparent in some studies but not others, and is not convincingly supported by clinical studies as they rarely include cases with lesions confined to the parietal lobe. We compared Speech with non-communicative repetitive tongue movements (Tongue). The data were analyzed with both univariate contrasts between conditions and probabilistic independent component analysis (ICA). The former indicated decreased activity of left IPC during Speech relative to Tongue. However, the ICA revealed a Speech component in which there was correlated activity between left IPC, frontal and temporal cortices known to be involved in language. Therefore, although net synaptic activity throughout the left IPC may not increase above baseline conditions during Speech, one or more local systems within this region are involved, evidenced by the correlated activity with other language regions.

Network dysfunction predicts speech production after left hemisphere stroke

Objective: To investigate the role of multiple distributed brain networks, including the default mode, fronto-temporo-parietal, and cingulo-opercular networks, which mediate domain-general and task-specific processes during speech production after aphasic stroke. Methods: We conducted an observational functional MRI study to investigate the effects of a previous left hemisphere stroke on functional connectivity within and between distributed networks as patients described pictures. Study design included various baseline tasks, and we compared results to those of age-matched healthy participants performing the same tasks. We used independent component and psychophysiological interaction analyses. Results: Although activity within individual networks was not predictive of speech production, relative activity between networks was a predictor of both within-scanner and out-of-scanner language performance, over and above that predicted from lesion volume, age, sex, and years of education. Specifically, robust functional imaging predictors were the differential activity between the default mode network and both the left and right fronto-temporo-parietal networks, respectively activated and deactivated during speech. We also observed altered between-network functional connectivity of these networks in patients during speech production. Conclusions: Speech production is dependent on complex interactions among widely distributed brain networks, indicating that residual speech production after stroke depends on more than the restoration of local domain-specific functions. Our understanding of the recovery of function following focal lesions is not adequately captured by consideration of ipsilesional or contralesional brain regions taking over lost domain-specific functions, but is perhaps best considered as the interaction between what remains of domain-specific networks and domain-general systems that regulate behavior.

MICROGLIA IN GEMISTOCYTIC ASTROCYTOMAS

OBJECTIVEAlthough gemistocytic astrocytomas are graded as World Health Organization II astrocytomas, they behave more aggressively than other astrocytomas. Their proliferative potential is low, and it remains an intriguing question why these tumors are so biologically “successful.” They show a high mutation rate of the P53 gene, cytological abnormalities, and frequent perivascular mononuclear infiltrates. Microglial cells, a feature of this astrocytoma variant, are of increasing interest in the context of glioma growth. METHODSWe selected 23 tumor biopsies from 201 samples obtained from patients with gemistocytic astrocytomas operated at Mayo Clinic between 1985 and 1998. These tumors were formerly analyzed for P53 mutations, p53 protein, and proliferative activity (9). Immunolabeling for three microglial markers, including CR3/43, Ki-M1P, and iba1, was performed on adjacent tissue sections. In addition, in situ hybridization for the α-chain of the major histocompatibility complex (MHC) Class II molecule recognized by the CR3/43 monoclonal antibody was performed. RESULTSA high number of microglia was detected in gemistocytic astrocytomas. More microglia were present if the fraction of gemistocytic tumor cells was high (correlation coefficient = 0.699; P < 0.0002). Interestingly, a number of gemistocytes were immunoreactive for MHC Class II molecules, an observation confirmed by in situ hybridization. Importantly, the higher the number of Class II immunoreactive gemistocytes, the fewer Class II positive microglial cells could be detected (correlation coefficient = −0.5649; P < 0.005). CONCLUSIONOur results support the view that gemistocytic astrocytomas contain unusually high numbers of microglial cells. We propose that the finding of aberrant MHC Class II expression by gemistocytic tumor cells correlates with a loss of immune-competent MHC Class II-expressing microglia. This may be related to the especially poor prognosis of gemistocytic astrocytomas for which induction of T cell anergy could provide one explanation.

Measuring vascular reactivity with breath-holds after stroke: A method to aid interpretation of group-level BOLD signal changes in longitudinal fMRI studies

Blood oxygenation level‐dependent (BOLD) contrast functional magnetic resonance imaging (fMRI) is a widely used technique to map brain function, and to monitor its recovery after stroke. Since stroke has a vascular etiology, the neurovascular coupling between cerebral blood flow and neural activity may be altered, resulting in uncertainties when interpreting longitudinal BOLD signal changes. The purpose of this study was to demonstrate the feasibility of using a recently validated breath‐hold task in patients with stroke, both to assess group level changes in cerebrovascular reactivity (CVR) and to determine if alterations in regional CVR over time will adversely affect interpretation of task‐related BOLD signal changes. Three methods of analyzing the breath‐hold data were evaluated. The CVR measures were compared over healthy tissue, infarcted tissue and the peri‐infarct tissue, both sub‐acutely (∼2 weeks) and chronically (∼4 months). In this cohort, a lack of CVR differences in healthy tissue between the patients and controls indicates that any group level BOLD signal change observed in these regions over time is unlikely to be related to vascular alterations. CVR was reduced in the peri‐infarct tissue but remained unchanged over time. Therefore, although a lack of activation in this region compared with the controls may be confounded by a reduced CVR, longitudinal group‐level BOLD changes may be more confidently attributed to neural activity changes in this cohort. By including this breath‐hold‐based CVR assessment protocol in future studies of stroke recovery, researchers can be more assured that longitudinal changes in BOLD signal reflect true alterations in neural activity. Hum Brain Mapp 36:1755–1771, 2015.

Semantic retrieval during overt picture description: Left anterior temporal or the parietal lobe?

Retrieval of semantic representations is a central process during overt speech production. There is an increasing consensus that an amodal semantic ‘hub’ must exist that draws together modality-specific representations of concepts. Based on the distribution of atrophy and the behavioral deficit of patients with the semantic variant of fronto-temporal lobar degeneration, it has been proposed that this hub is localized within both anterior temporal lobes (ATL), and is functionally connected with verbal ‘output’ systems via the left ATL. An alternative view, dating from Geschwinds proposal in 1965, is that the angular gyrus (AG) is central to object-based semantic representations. In this fMRI study we examined the connectivity of the left ATL and parietal lobe (PL) with whole brain networks known to be activated during overt picture description. We decomposed each of these two brain volumes into 15 regions of interest (ROIs), using independent component analysis. A dual regression analysis was used to establish the connectivity of each ROI with whole brain-networks. An ROI within the left anterior superior temporal sulcus (antSTS) was functionally connected to other parts of the left ATL, including anterior ventromedial left temporal cortex (partially attenuated by signal loss due to susceptibility artifact), a large left dorsolateral prefrontal region (including ‘classic’ Brocas area), extensive bilateral sensory-motor cortices, and the length of both superior temporal gyri. The time-course of this functionally connected network was associated with picture description but not with non-semantic baseline tasks. This system has the distribution expected for the production of overt speech with appropriate semantic content, and the auditory monitoring of the overt speech output. In contrast, the only left PL ROI that showed connectivity with brain systems most strongly activated by the picture-description task, was in the superior parietal lobe (supPL). This region showed connectivity with predominantly posterior cortical regions required for the visual processing of the pictorial stimuli, with additional connectivity to the dorsal left AG and a small component of the left inferior frontal gyrus. None of the other PL ROIs that included part of the left AG were activated by Speech alone. The best interpretation of these results is that the left antSTS connects the proposed semantic hub (specifically localized to ventral anterior temporal cortex based on clinical neuropsychological studies) to posterior frontal regions and sensory-motor cortices responsible for the overt production of speech.

Impact of UK academic foundation programmes on aspirations to pursue a career in academia

Medical Education 2010: 44: 996–1005