Cerebral compensation during motor function in Friedreich ataxia: The IMAGE‐FRDA study

Background : Friedreich ataxia is characterized by progressive motor incoordination that is linked to peripheral, spinal, and cerebellar neuropathology. Cerebral abnormalities are also reported in Friedreich ataxia, but their role in disease expression remains unclear. Methods : In this cross‐sectional functional magnetic resonance imaging study, 25 individuals with Friedreich ataxia and 33 healthy controls performed simple (self‐paced single‐finger) and complex (visually cued multifinger) tapping tasks to respectively gauge basic and attentionally demanding motor behavior. For each task, whole brain functional activations were compared between groups and correlated with disease severity and offline measures of motor dexterity. Results : During simple finger tapping, cerebral hyperactivation in individuals with Friedreich ataxia at the lower end of clinical severity and cerebral hypoactivation in those more severely affected was observed in premotor/ventral attention brain regions, including the supplementary motor area and anterior insula. Greater activation in this network correlated with greater offline finger tapping precision. Complex, attentionally demanding finger tapping was also associated with cerebral hyperactivation, but in this case within dorsolateral prefrontal regions of the executive control network and superior parietal regions of the dorsal attention system. Greater offline motor precision was associated with less activation in the dorsal attention network. Discussion : Compensatory activity is evident in the cerebral cortex in individuals with Friedreich ataxia. Early compensation followed by later decline in premotor/ventral attention systems demonstrates capacity‐limited neural reserve, while the additional engagement of higher order brain networks is indicative of compensatory task strategies. Network‐level changes in cerebral brain function thus potentially serve to mitigate the impact of motor impairments in Friedreich ataxia. © 2017 International Parkinson and Movement Disorder Society     

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion‐tensor, magnetization transfer, and T1‐weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole‐brain voxel‐wise between‐group comparisons and correlations with disease severity, onset age, and gene triplet‐repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel‐level pattern of between‐group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri‐dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.     

Social cognition and the cerebellum: A meta‐analytic connectivity analysis

This meta‐analytic connectivity modeling (MACM) study explores the functional connectivity of the cerebellum with the cerebrum in social cognitive processes. In a recent meta‐analysis, Van Overwalle, Baetens, Mariën, and Vandekerckhove ( 2014 ) documented that the cerebellum is implicated in social processes of “body” reading (mirroring; e.g., understanding other persons' intentions from observing their movements) and “mind” reading (mentalizing, e.g., inferring other persons' beliefs, intentions or personality traits, reconstructing persons' past, future, or hypothetical events). In a recent functional connectivity study, Buckner et al. ( 2011 ) offered a novel parcellation of cerebellar topography that substantially overlaps with the cerebellar meta‐analytic findings of Van Overwalle et al. ( 2014 ). This overlap suggests that the involvement of the cerebellum in social reasoning depends on its functional connectivity with the cerebrum. To test this hypothesis, we explored the meta‐analytic co‐activations as indices of functional connectivity between the cerebellum and the cerebrum during social cognition. The MACM results confirm substantial and distinct connectivity with respect to the functions of (a) action understanding (“body” reading) and (b) mentalizing (“mind” reading). The consistent and strong connectivity findings of this analysis suggest that cerebellar activity during social judgments reflects distinct mirroring and mentalizing functionality, and that these cerebellar functions are connected with corresponding functional networks in the cerebrum. Hum Brain Mapp 36:5137–5154, 2015. © 2015 Wiley Periodicals, Inc.     

Working memory‐related changes in functional connectivity persist beyond task disengagement

We examined whether altered connectivity in functional networks during working memory performance persists following conclusion of that performance, into a subsequent resting state. We conducted functional magnetic resonance imaging (fMRI) in 50 young adults during an initial resting state, followed by an N‐back working memory task and a subsequent resting state, in order to examine changes in functional connectivity within and between the default‐mode network (DMN) and the task‐positive network (TPN) across the three states. We found that alterations in connectivity observed during the N‐back task persisted into the subsequent resting state within the TPN and between the DMN and TPN, but not within the DMN. Further, both speed of working memory performance and TPN connectivity strength during the N‐back task predicted connectivity strength in the subsequent resting state. Finally, DMN connectivity measured before and during the N‐back task predicted individual differences in self‐reported inattentiveness, but this association was not found during the post‐task resting state. Together, these findings have important implications for models of how the brain recovers following effortful cognition, as well as for experimental designs using resting and task scans. Hum Brain Mapp 35:1004–1017, 2014. © 2012 Wiley Periodicals, Inc.     

Cerebellar–cortical dysconnectivity in resting‐state associated with sensorimotor tasks in schizophrenia

Abnormalities of cerebellar function have been implicated in the pathophysiology of schizophrenia. Since the cerebellum has afferent and efferent projections to diverse brain regions, abnormalities in cerebellar lobules could affect functional connectivity with multiple functional systems in the brain. Prior studies, however, have not examined the relationship of individual cerebellar lobules with motor and nonmotor resting‐state functional networks. We evaluated these relationships using resting‐state fMRI in 30 patients with a schizophrenia‐spectrum disorder and 37 healthy comparison participants. For connectivity analyses, the cerebellum was parcellated into 18 lobular and vermal regions, and functional connectivity of each lobule to 10 major functional networks in the cerebrum was evaluated. The relationship between functional connectivity measures and behavioral performance on sensorimotor tasks (i.e., finger‐tapping and postural sway) was also examined. We found cerebellar–cortical hyperconnectivity in schizophrenia, which was predominantly associated with Crus I, Crus II, lobule IX, and lobule X. Specifically, abnormal cerebellar connectivity was found to the cerebral ventral attention, motor, and auditory networks. This cerebellar–cortical connectivity in the resting‐state was differentially associated with sensorimotor task‐based behavioral measures in schizophrenia and healthy comparison participants—that is, dissociation with motor network and association with nonmotor network in schizophrenia. These findings suggest that functional association between individual cerebellar lobules and the ventral attentional, motor, and auditory networks is particularly affected in schizophrenia. They are also consistent with dysconnectivity models of schizophrenia suggesting cerebellar contributions to a broad range of sensorimotor and cognitive operations.     

Functional magnetic resonance imaging of working memory in Huntington's disease: Cross‐sectional data from the IMAGE‐HD study

We used functional magnetic resonance imaging (fMRI) to investigate spatial working memory (WM) in an N–BACK task (0, 1, and 2‐BACK) in premanifest Huntington's disease (pre‐HD, n = 35), early symptomatic Huntington's disease (symp‐HD, n = 23), and control (n = 32) individuals. Overall, both WM conditions (1‐BACK and 2‐BACK) activated a large network of regions throughout the brain, common to all groups. However, voxel‐wise and time‐course analyses revealed significant functional group differences, despite no significant behavioral performance differences. During 1‐BACK, voxel‐wise blood‐oxygen‐level‐dependent (BOLD) signal activity was significantly reduced in a number of regions from the WM network (inferior frontal gyrus, anterior insula, caudate, putamen, and cerebellum) in pre‐HD and symp‐HD groups, compared with controls; however, time‐course analysis of the BOLD response in the dorsolateral prefrontal cortex (DLPFC) showed increased activation in symp‐HD, compared with pre‐HD and controls. The pattern of reduced voxel‐wise BOLD activity in pre‐HD and symp‐HD, relative to controls, became more pervasive during 2‐BACK affecting the same structures as in 1‐BACK, but also incorporated further WM regions (anterior cingulate gyrus, parietal lobe and thalamus). The DLPFC BOLD time‐course for 2‐BACK showed a reversed pattern to that observed in 1‐BACK, with a significantly diminished signal in symp‐HD, relative to pre‐HD and controls. Our findings provide support for functional brain reorganisation in cortical and subcortical regions in both pre‐HD and symp‐HD, which are modulated by task difficulty. Moreover, the lack of a robust striatal BOLD signal in pre‐HD may represent a very early signature of change observed up to 15 years prior to clinical diagnosis. Hum Brain Mapp 35:1847–1864, 2014. © 2013 Wiley Periodicals, Inc.     

The relationship between level of processing and hippocampal–cortical functional connectivity during episodic memory formation in humans

New episodic memory traces represent a record of the ongoing neocortical processing engaged during memory formation (encoding). Thus, during encoding, deep (semantic) processing typically establishes more distinctive and retrievable memory traces than does shallow (perceptual) processing, as assessed by later episodic memory tests. By contrast, the hippocampus appears to play a processing‐independent role in encoding, because hippocampal lesions impair encoding regardless of level of processing. Here, we clarified the neural relationship between processing and encoding by examining hippocampal–cortical connectivity during deep and shallow encoding. Participants studied words during functional magnetic resonance imaging and freely recalled these words after distraction. Deep study processing led to better recall than shallow study processing. For both levels of processing, successful encoding elicited activations of bilateral hippocampus and left prefrontal cortex, and increased functional connectivity between left hippocampus and bilateral medial prefrontal, cingulate and extrastriate cortices. Successful encoding during deep processing was additionally associated with increased functional connectivity between left hippocampus and bilateral ventrolateral prefrontal cortex and right temporoparietal junction. In the shallow encoding condition, on the other hand, pronounced functional connectivity increases were observed between the right hippocampus and the frontoparietal attention network activated during shallow study processing. Our results further specify how the hippocampus coordinates recording of ongoing neocortical activity into long‐term memory, and begin to provide a neural explanation for the typical advantage of deep over shallow study processing for later episodic memory. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Bridging the gap between functional and anatomical features of cortico‐cerebellar circuits using meta‐analytic connectivity modeling

Theories positing that the cerebellum contributes to cognitive as well as motor control are driven by two sources of information: (1) studies highlighting connections between the cerebellum and both prefrontal and motor territories, (2) functional neuroimaging studies demonstrating cerebellar activations evoked during the performance of both cognitive and motor tasks. However, almost no studies to date have combined these two sources of information and investigated cortico‐cerebellar connectivity during task performance. Through the use of a novel neuroimaging tool (Meta‐Analytic Connectivity Modelling) we demonstrate for the first time that cortico‐cerebellar connectivity patterns seen in anatomical studies and resting fMRI are also present during task performance. Consistent with human and nonhuman primate anatomical studies cerebellar lobules Crus I and II were significantly coactivated with prefrontal and parietal cortices during task performance, whilst lobules HV, HVI, HVIIb, and HVIII were significantly coactivated with the pre‐ and postcentral gyrus. An analysis of the behavioral domains showed that these circuits were driven by distinct tasks. Prefrontal‐parietal‐cerebellar circuits were more active during cognitive and emotion tasks whilst motor‐cerebellar circuits were more active during action execution tasks. These results highlight the separation of prefrontal and motor cortico‐cerebellar loops during task performance, and further demonstrate that activity within these circuits relates to distinct functions. Hum Brain Mapp 35:3152–3169, 2014. © 2013 Wiley Periodicals, Inc.     

Fronto‐cingulate effective connectivity in obsessive compulsive disorder: A study with fMRI and dynamic causal modeling

Evidence suggests that obsessive compulsive disorder (OCD) is associated with an overactive error control system. A key role in error detection and control has been ascribed to the fronto‐cingulate system. However, the exact functional interplay between the single components of this network in OCD is largely unknown. Therefore, the present study combined a univariate data analysis and effective connectivity analysis using dynamic causal modeling (DCM) to examine error control in 21 patients with OCD and 21 matched healthy controls. All subjects performed an adapted version of the Stroop color‐word task while undergoing fMRI scans. Enhanced activation in the fronto‐cingulate system could be detected in OCD patients during the incongruent task condition. Additionally, task‐related modulation of effective connectivity from the dorsal ACC to left DLPFC was significantly stronger in OCD patients. These findings are consistent with an overactive error control system in OCD subserving suppression of prepotent responses during decision‐making. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Superior temporal lobe dysfunction and frontotemporal dysconnectivity in subjects at risk of psychosis and in first‐episode psychosis

Background: Superior temporal lobe dysfunction is a robust finding in functional neuroimaging studies of schizophrenia and is thought to be related to a disruption of fronto‐temporal functional connectivity. However, the stage of the disorder at which these functional alterations occur is unclear. We addressed this issue by using functional MRI (fMRI) to study subjects in the prodromal and first episode phases of schizophrenia. Methods: Subjects with an at risk mental state (ARMS) for psychosis, a first psychotic episode (FEP), and controls were studied using fMRI while performing a working memory task. Activation in the superior temporal gyrus (STG) was assessed using statistical parametric mapping, and its relationship to frontal activation was examined using dynamic causal modeling. Results: The STG was differentially engaged across the three groups. There was deactivation of this region during the task in controls, whereas subjects with FEP showed activation and the response in subjects with ARMS was intermediately relative to the two other groups. There were corresponding differences in the effective connectivity between the STG and the middle frontal gyrus across the three groups, with a negative coupling between these areas in controls, a positive coupling in the FEP group, and an intermediate value in the ARMS group. Conclusions: A failure to deactivate the superior temporal lobe during tasks that engage prefrontal cortex is evident at the onset of schizophrenia and may reflect a disruption of fronto‐temporal connectivity. Qualitatively similar alterations are evident in people with prodromal symptoms of the disorder. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Altered corticomotor‐cerebellar integrity in young ataxia telangiectasia patients

Magnetic resonance imaging (MRI) research in identifying altered brain structure and function in ataxia‐telangiectasia, an autosomal recessive neurodegenerative disorder, is limited. Diffusion‐weighted MRI were obtained from 11 ataxia telangiectasia patients (age range, 7‐22 years; mean, 12 years) and 11 typically developing age‐matched participants (age range, 8‐23 years; mean, 13 years). Gray matter volume alterations in patients were compared with those of healthy controls using voxel‐based morphometry, whereas tract‐based spatial statistics was employed to elucidate white matter microstructure differences between groups. White matter microstructure was probed using quantitative fractional anisotropy and mean diffusivity measures. Reduced gray matter volume in both cerebellar hemispheres and in the precentral‐postcentral gyrus in the left cerebral hemisphere was observed in ataxia telangiectasia patients compared with controls (P < 0.05, corrected for multiple comparisons). A significant reduction in fractional anisotropy in the cerebellar hemispheres, anterior/posterior horns of the medulla, cerebral peduncles, and internal capsule white matter, particularly in the left posterior limb of the internal capsule and corona radiata in the left cerebral hemisphere, was observed in patients compared with controls (P < 0.05). Mean diffusivity differences were observed within the left cerebellar hemisphere and the white matter of the superior lobule of the right cerebellar hemisphere (P < 0.05). Cerebellum‐localized gray matter changes are seen in young ataxia telangiectasia patients along with white matter tract degeneration projecting from the cerebellum into corticomotor regions. The lack of cortical involvement may reflect early‐stage white matter motor pathway degeneration within young patients. © 2014 International Parkinson and Movement Disorder Society     

Fronto‐temporal dysregulation in asymptomatic bipolar I patients: A paired associate functional MRI study

Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face‐name paired associate task, which allows for the dissociation of encoding and recall‐related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task‐related brain regions during encoding. During recognition, bipolar patients under‐activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo‐activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition‐related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over‐engaged dorsolateral prefrontal regions when learning face‐name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long‐term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.     

Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression.

BACKGROUND: A large number of studies suggest the presence of deficits in dorsolateral prefrontal cortex function during performance of working memory tasks in individuals with schizophrenia. However, working memory deficits may also present in other psychiatric disorders, such as major depression. It is not clear whether people with major depression also demonstrate impaired prefrontal activation during performance of working memory tasks. METHODS: We used functional magnetic resonance imaging to assess the patterns of cortical activation associated with the performance of a 2-back version of the N-Back task (working memory) in 38 individuals with schizophrenia and 14 with major depression. RESULTS: We found significant group differences in the activation of dorsolateral prefrontal cortex associated with working memory performance. Consistent with prior research, participants with schizophrenia failed to show activation of right dorsolateral prefrontal cortex in response to working memory tasks demands, whereas those with major depression showed clear activation of right and left dorsolateral prefrontal cortex as well as bilateral activation of inferior and superior frontal cortex. CONCLUSIONS: During performance of working memory tasks, deficits in prefrontal activation, including dorsolateral regions, are more severe in participants with schizophrenia (most of whom were recently released outpatients) than in unmedicated outpatients with acute nonpsychotic major depression.     

Characterization of whole‐brain task‐modulated functional connectivity in response to nociceptive pain: A multisensory comparison study

Previous functional magnetic resonance imaging (fMRI) studies have shown that brain responses to nociceptive pain, non‐nociceptive somatosensory, visual, and auditory stimuli are extremely similar. Actually, perception of external sensory stimulation requires complex interactions among distributed cortical and subcortical brain regions. However, the interactions among these regions elicited by nociceptive pain remain unclear, which limits our understanding of mechanisms of pain from a brain network perspective. Task fMRI data were collected with a random sequence of intermixed stimuli of four sensory modalities in 80 healthy subjects. Whole‐brain psychophysiological interaction analysis was performed to identify task‐modulated functional connectivity (FC) patterns for each modality. Task‐modulated FC strength and graph‐theoretical‐based network properties were compared among the four modalities. Lastly, we performed across‐sensory‐modality prediction analysis based on the whole‐brain task‐modulated FC patterns to confirm the specific relationship between brain patterns and sensory modalities. For each sensory modality, task‐modulated FC patterns were distributed over widespread brain regions beyond those typically activated or deactivated during the stimulation. As compared with the other three sensory modalities, nociceptive stimulation exhibited significantly different patterns (more widespread and stronger FC within the cingulo‐opercular network, between cingulo‐opercular and sensorimotor networks, between cingulo‐opercular and emotional networks, and between default mode and emotional networks) and global property (smaller modularity). Further, a cross‐sensory‐modality prediction analysis found that task‐modulated FC patterns could predict sensory modality at the subject level successfully. Collectively, these results demonstrated that the whole‐brain task‐modulated FC is preferentially modulated by pain, thus providing new insights into the neural mechanisms of pain processing.