No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Localizing parkinsonism based on focal brain lesions
Abstract
Bradykinesia, rigidity, and tremor frequently co-occur, a clinical syndrome known as parkinsonism. Because this syndrome is commonly seen in Parkinson’s disease, symptoms are often attributed to cell loss in the substantia nigra. However, parkinsonism occurs in several other neurological disorders and often fails to correlate with nigrostriatal pathology, raising the question of which brain region(s) cause this syndrome. Here, we studied cases of new-onset parkinsonism following focal brain lesions. We identified 29 cases, only 31% of which hit the substantia nigra. Lesions were located in a variety of different cortical and subcortical locations. To determine whether these heterogeneous lesion locations were part of a common brain network, we leveraged the human brain connectome and a recently validated technique termed lesion network mapping. Lesion locations causing parkinsonism were functionally connected to a common network of regions including the midbrain, basal ganglia, cingulate cortex, and cerebellum. The most sensitive and specific connectivity was to the claustrum. This lesion connectivity pattern matched atrophy patterns seen in Parkinson’s disease, progressive supranuclear palsy, and multiple system atrophy, suggesting a shared neuroanatomical substrate for parkinsonism. Lesion connectivity also predicted medication response and matched the pattern of effective deep brain stimulation, suggesting relevance as a treatment target. Our results, based on causal brain lesions, lend insight into the localization of parkinsonism, one of the most common syndromes in neurology. Because many patients with parkinsonism fail to respond to dopaminergic medication, these results may aid the development of alternative treatments.
... This technique, termed lesion network mapping (LNM), is particularly helpful when lesions causing similar symptoms occur in multiple different brain locations. It has been successfully used to elucidate lesioninduced prosopagnosia (34), amnesia (35), movement disorders (36), and a variety of other symptoms and can identify therapeutic targets for brain stimulation (37)(38)(39). In this study, we applied LNM to a cohort of Vietnam veterans with a history of penetrating head trauma and postinjury aggression scores to assess whether lesion locations associated with aggression map to specific brain regions and networks. ...
... deep brain electrical stimulation of a given brain area induces a functional inhibition effect akin to a lesion (82). This is consistent with an expanding body of literature suggesting that lesion locations and DBS sites that cause similar effects converge on common brain networks (36,51,(83)(84)(85). ANT has extensive white matter connections with the limbic structures and orbitomedial PFC and contributes to reciprocal hippocampal-prefrontal interactions involved in emotion (86). ...
... A similar bootstrap approach has been described in previous study (35)(36)(37). Briefly, the null hypothesis that the correlation of irritability equals the mean correlation of the remaining symptoms was generated. ...
... The main advantage in studying brain lesions is that they can provide causal inference between the damaged brain area and the resulting clinical symptoms 11 . For example, lesions causing parkinsonism and hemichorea have confirmed the role of damage of the nigrostriatal tract and subthalamic nucleus (STN) in these symptoms, respectively 4,13 . ...
... This coordinate mapping technique is similar to 'lesion network mapping' discussed above, examining the functional connections of lesions causing movement disorders, yet an advantage of this approach is that it can be applied to multimodal neuroimaging data in idiopathic disorders. Currently available findings suggest that these techniques converge on the same brain networks in movement disorders, but this is an area of ongoing investigation 4,11,12,15 . ...
... Evidence gathered across these levels can establish symptom-specific networks in movement disorders. Prior research studies provided as examples of each level of evidence: Vaillancourt et al.154 ; Prodoehl et al.155 ; Nagano-Saito et al.156 ; Abe et al.157 ; Möller et al.158 ; Matthews et al.159 ; Niethammer et al.64 ; Joutsa et al.4 ; Bédard et al.160 ; Filip et al.161 ; Chu et al.120 ; Park et al.162 . ...
Movement disorders, such as Parkinson's disease, essential tremor, and dystonia, are characterized by their predominant motor symptoms, yet diseases causing abnormal movement also encompass several other symptoms, including non-motor symptoms. Here we review recent advances from studies of brain lesions, neuroimaging, and neuromodulation that provide converging evidence on symptom-specific brain networks in movement disorders. Although movement disorders have traditionally been conceptualized as disorders of the basal ganglia, cumulative data from brain lesions causing parkinsonism, tremor and dystonia have now demonstrated that this view is incomplete. Several recent studies have shown that lesions causing a given movement disorder occur in heterogeneous brain locations, but disrupt common brain networks, which appear to be specific to each motor phenotype. In addition, findings from structural and functional neuroimaging in movement disorders have demonstrated that brain abnormalities extend far beyond the brain networks associated with the motor symptoms. In fact, neuroimaging findings in each movement disorder are strongly influenced by the constellation of patients' symptoms that also seem to map to specific networks rather than individual anatomical structures or single neurotransmitters. Finally, observations from deep brain stimulation have demonstrated that clinical changes, including both symptom improvement and side effects, are dependent on the modulation of large-scale networks instead of purely local effects of the neuromodulation. Combined, this multimodal evidence suggests that symptoms in movement disorders arise from distinct brain networks, encouraging multimodal imaging studies to better characterize the underlying symptom-specific mechanisms and individually tailor treatment approaches.
... 17,18 A recently developed method, lesion network mapping, extends the use of focal brain lesion location information by studying the network connections common to a group of lesions. 15,19 Lesion network mapping has successfully been applied to localize multiple symptoms and signs, 15,20 including movement disorders, [21][22][23][24][25] neuropsychiatric disorders, [26][27][28] consciousness 29,30 and other behavioural changes. 31,32 Importantly, the networks identified using lesion network mapping seem to consistently generalize across primary brain disorders causing similar symptoms, suggesting a shared neural substrate for a symptom despite distinct aetiologies. ...
... 31,32 Importantly, the networks identified using lesion network mapping seem to consistently generalize across primary brain disorders causing similar symptoms, suggesting a shared neural substrate for a symptom despite distinct aetiologies. 21,23 Finally, investigating lesion connectivity has been shown to identify efficacious neurosurgical treatment targets, suggesting relevance for treatment. 23,24,33 Our first goal was to test if brain lesions causing acquired neurogenic stuttering connect to a common brain network that could lend insight into the neural substrates of stuttering. ...
... 21,23 Finally, investigating lesion connectivity has been shown to identify efficacious neurosurgical treatment targets, suggesting relevance for treatment. 23,24,33 Our first goal was to test if brain lesions causing acquired neurogenic stuttering connect to a common brain network that could lend insight into the neural substrates of stuttering. To accomplish this, we applied lesion network mapping to two independent datasets of acquired neurogenic stuttering following stroke. ...
Stuttering affects approximately 1 in 100 adults and can result in significant communication problems and social anxiety. It most often occurs as a developmental disorder but can also be caused by focal brain damage. These latter cases may lend unique insight into the brain regions causing stuttering.
Here, we investigated the neuroanatomical substrate of stuttering using three independent datasets: (i) case reports from the published literature of acquired neurogenic stuttering following stroke (n = 20, 14 males/six females, 16–77 years); (ii) a clinical single study cohort with acquired neurogenic stuttering following stroke (n = 20, 13 males/seven females, 45–87 years); and (iii) adults with persistent developmental stuttering (n = 20, 14 males/six females, 18–43 years). We used the first two datasets and lesion network mapping to test whether lesions causing acquired stuttering map to a common brain network. We then used the third dataset to test whether this lesion-based network was relevant to developmental stuttering.
In our literature dataset, we found that lesions causing stuttering occurred in multiple heterogeneous brain regions, but these lesion locations were all functionally connected to a common network centred around the left putamen, including the claustrum, amygdalostriatal transition area and other adjacent areas. This finding was shown to be specific for stuttering (PFWE < 0.05) and reproducible in our independent clinical cohort of patients with stroke-induced stuttering (PFWE < 0.05), resulting in a common acquired stuttering network across both stroke datasets. Within the common acquired stuttering network, we found a significant association between grey matter volume and stuttering impact for adults with persistent developmental stuttering in the left posteroventral putamen, extending into the adjacent claustrum and amygdalostriatal transition area (PFWE < 0.05).
We conclude that lesions causing acquired neurogenic stuttering map to a common brain network, centred to the left putamen, claustrum and amygdalostriatal transition area. The association of this lesion-based network with symptom severity in developmental stuttering suggests a shared neuroanatomy across aetiologies.
... Background Parkinsonism refers to a group of neurological disorders characterized by motor symptoms such as tremor, bradykinesia (slowness of movement), rigidity, and postural instability (1). While the primary cause of Parkinsonism is often associated with degenerative conditions like Parkinson's disease, it's essential to consider other potential etiologies, including neoplasias of the central nervous system (CNS) (2,3). ...
... Tumors within the CNS can disrupt the normal functioning of neural circuits, leading to a range of motor and non-motor symptoms, including parkinsonism (1,3,4). ...
... A study on lesion-induced parkinsonism found that over 90% of lesion locations were connected to the midbrain, basal ganglia, anterior cingulate cortex and cerebellum. These spots are part of an intrinsically connected brain network, with connectivity to the claustrum being the most sensitive and speci c marker of lesion-induced parkinsonism (1). Animal studies have demonstrated connections of supramammillary nucleus (SuM), which is an area right below the hypothalamus, to the claustrum. ...
Background: Parkinsonism is more often caused by lesions affecting the basal ganglia but may also occur in lesions outside of this region.
Case report: We report a case of a 17-year-old boy that presented with imbalance, slowing of movements, and abnormal posturing of the right arm. Neuroimaging revealed a lesion involving the right hypothalamus, with mild volume loss of the left thalamus and putamen.
Discussion: Parkinsonism caused by brain tumors is very rare. To our knowledge there is no previous report of germinomas causing parkinsonism or dystonia. Most previously reported cases of parkinsonism secondary to tumors had a favorable outcome after tumor excision, but dopaminergic treatment was ineffective. This challenging case highlights the possibility of secondary causes for dystonia-parkinsonism and the possibility of lesions outside the main basal ganglia circuit presenting with parkinsonism.
... The most common cause of parkinsonism is Parkinson's disease, a neurological disorder characterized by degeneration of dopamine neurons in the pars compacta of the substantia nigra (SNpc). 1 However, parkinsonism is not specific to idiopathic loss of dopamine neurons and may have different pathophysiological etiologies. 2 One possible and rare cause of hemiparkinsonism is direct mechanical compression of the basal ganglia. [3][4][5][6] Different spaceoccupying lesions causing parkinsonism have been described in the literature: tumors, large arachnoid cysts, giant aneurysms, and chronic subdural hematoma. ...
... Joutsa et al. 2 studied cases of new-onset parkinsonism caused by focal brain lesions (located in a variety of different cortical and subcortical locations). When analyzing the connectivity of these cases, lesions causing parkinsonism were connected to several regions, but the most sensitive and specific connectivity was to the claustrum. ...
... These findings highlight the claustrum as a potential key region in the development of parkinsonism. 2 When analyzing the MRI of our patient, the claustrum cannot be identified due to the massive tumor compression. We assume the claustrum compression to be a relevant and early cofactor in the development of our patient's hemiparkinsonism. ...
BACKGROUND: The etiologies of parkinsonism are diverse. A possible and rare cause of hemiparkinsonism is mechanical compression of the basal ganglia and its connecting white matter tracts. The authors present a case of hemiparkinsonism caused by a lateral sphenoid wing meningioma, discuss the underlying pathophysiology based on tractography, and systematically review the existing literature.
OBSERVATIONS: A 59-year-old female was referred for a left-sided tremor of the hand, accompanied by a cogwheel rigidity of the left arm. Symptomatology appeared 1 year earlier and worsened in the previous 6 months, finally also showing involvement of the left leg. Magnetic resonance imaging (MRI) showed a space-occupying suspected meningioma originating from the right lateral sphenoid wing and compressing the ipsilateral striatum. Tractography studies contributed to elucidate the underlying pathophysiology. Resection of the meningioma could be performed without complications. At the 4-month follow-up, the patient’s hemiparkinsonism had completely recovered.
LESSONS: An intracranial space-occupying lesion may be a rare cause of hemiparkinsonism. In new-onset parkinsonism, especially if a secondary form is suspected, brain MRI should be performed promptly to avoid misdiagnosis and treatment. Tractography studies help understand the underlying pathophysiology. After surgical decompression of the affected structures, symptoms can recover completely.
... Imaging clinical correlation analysis is challenging due to clinical and neuroimaging heterogeneity. PSMDs were traditionally thought to be caused by lesions in specific anatomical brain structures, more recent evidence has shown that this is often not true [52]. Similar clinical phenotypes are seen with lesions in heterogeneous anatomical locations, and clinical heterogeneity is seen with lesions affecting the same anatomical structures [4]. ...
... Similar clinical phenotypes are seen with lesions in heterogeneous anatomical locations, and clinical heterogeneity is seen with lesions affecting the same anatomical structures [4]. For example, only a minority of patients with hemichoreahemiballism have lesions in the subthalamic nucleus, and lesions in the globus pallidus have led to multiple abnormal movements [52]. It has been estimated that lesion locations considered atypical can occur in approximately half of PSMD cases [4], but these estimates are based on limited data, which can include diagnostic and reporting biases. ...
Background: A prospective observational study recruited patients with acute stroke. Patients were assessed for the presence of post-stroke movement disorders PSMDs during the first week of stroke.
This study aimed to identify the frequency, clinical characteristics, and neuroimaging of early PSMDs (within the first week) and followed for 1 year.
Results: A total of 600 patients were recruited; 21 patients (3.5%) with PSMDs were detected. Thirteen (2.2%) patients presented with intention tremor/ataxia and eight (1.3%) presented with other movement disorders (most commonly, chorea and tremor). One patient presented with periodic left upper limb shaking with right subcortical watershed infarction, and one patient developed palatal myoclonus with right middle cerebral artery infarction. Patients with PSMDs had significantly lower stroke severity (NIHSS) and were more likely to have lacunar strokes (p < 0.001 and < 0.006, respectively) than patients without PSMDs. Early PSMDs were more associated with posterior circulation strokes (84.25%).
Conclusions: Early PSMDs are commonly hyperkinetic, more associated with small vessel disease, and less severe and posterior circulation strokes, implying their clinical importance for the proper management of stroke patients.
... Advances in lesion-based symptom localization have enabled the identification of brain networks causally linked with neurological symptoms [18,32]. Several studies have provided evidence that these networks may also be abnormal in idiopathic conditions causing similar symptoms, indicating that the findings are symptom-specific and generalize across etiologies [16,[33][34][35][36]. Lesion networks also seem to align with the known efficacious brain stimulation treatments, suggesting that targeting the causal network could be beneficial [16,33,34]. ...
... Advances in lesion-based symptom localization have enabled the identification of brain networks causally linked with neurological symptoms [18,32]. Several studies have provided evidence that these networks may also be abnormal in idiopathic conditions causing similar symptoms, indicating that the findings are symptom-specific and generalize across etiologies [16,[33][34][35][36]. Lesion networks also seem to align with the known efficacious brain stimulation treatments, suggesting that targeting the causal network could be beneficial [16,33,34]. The networks in movement disorders mostly centralize to the basal ganglia, making them difficult to reach via non-invasive brain stimulation. ...
... Secondary causes of parkinsonism have contributed to the knowledge on the pathophysiology and treatment of PD. Based on the pathological finding of a tuberculoma destroying the SN in a patient with contralateral parkinsonism, Edouard Brissaud put forward the hypothesis that the SN is the major site of pathology in PD. (182) Later recognition that lesions outside the nigrostriatal circuits may cause parkinsonism led to the understanding of parkinsonism as a network disorder (183). The identification of MPTP toxin, and further development of the primate model of PD, had a significant impact on the understanding of PD pathophysiology and led to the identification of the subthalamic nucleus as a target for deep brain stimulation (120). ...
... Over 90% of lesion locations were connected to the midbrain, BG, the anterior cingulate cortex and the cerebellum. However, connectivity to the claustrum was most sensitive and specific for lesion-induced parkinsonism, suggesting the claustrum as a potential novel therapeutic target (183). Using an analogous approach, lesions in areas functionally connected to the dorsal medial cerebellum were associated with freezing of gait (193). ...
Focal imaging abnormalities in patients with parkinsonism suggest secondary etiology and require a distinctive clinical approach to diagnosis and treatment. We review different entities presenting as secondary parkinsonism associated with structural brain lesions, with emphasis on the clinical course and neuroimaging findings. Secondary parkinsonism may be due to vascular causes, hydrocephalus, space-occupying lesions, metabolic causes (including acquired hepatocerebral degeneration, diabetic uremic encephalopathy, basal ganglia calcifications, osmotic demyelination syndrome), hypoxic-ischaemic brain injury, intoxications (including methanol, carbon monoxide, cyanide, carbon disulfide, manganese poisoning and illicit drugs), infections and immune causes. The onset can vary from acute to chronic. Both uni-and bilateral presentations are possible. Rigidity, bradykinesia and gait abnormalities are more common than rest tremor. Coexisting other movement disorders and additional associated neurological signs may point to the underlying diagnosis. Neuroimaging studies are an essential part in the diagnostic work-up of secondary parkinsonism and may point directly to the underlying etiology. We focus primarily on magnetic resonance imaging to illustrate how structural imaging combined with neurological assessment can lead to diagnosis. It is crucial that typical imaging abnormalities are recognized within the relevant clinical context. Many forms of secondary parkinsonism are reversible with elimination of the specific cause, while some may benefit from symptomatic treatment. This heterogeneous group of acquired disorders has also helped shape our knowledge of Parkinson’s disease and basal ganglia pathophysiology, while more recent findings in the field garner support for the network perspective on brain function and neurological disorders.
... For the parkinsonism network, 29 lesions associated with parkinsonism and 135 lesions not associated with parkinsonism were studied. 8 For the seizure network, 347 lesions associated with epilepsy and 1126 lesions not associated with epilepsy were studied. 9 The human connectome was used to identify the brain network connected to lesions associated with parkinsonism or seizures, a validated technique termed 'lesion network mapping.' 7 Parkinsonism versus seizure network . ...
... The copyright holder for this preprint this version posted May 3, 2024. ; https://doi.org/10.1101/2024.05.02.24306764 doi: medRxiv preprint Brain networks for parkinsonism 8,10 and seizures 9 were published previously and shown in Fig. 1A and B. To avoid bias, we first compared the spatial similarity between the published parkinsonism ( Fig. 1A) and seizure (Fig. 1B) networks using a spatial correlation (Pearson's r). ...
Recent epidemiological studies propose an association between parkinsonism and seizures, but the direction of this association is unclear. Focal brain lesions causing new-onset parkinsonism versus seizures may provide a unique perspective on the causal relationship between the two symptoms and involved brain networks. We studied lesions causing parkinsonism versus lesions causing seizures and utilized human connectome data to identify their connected brain networks. Brain networks for parkinsonism and seizures were compared using spatial correlations on a group and individual lesion level. Lesions not associated with either symptom were used as controls. Lesion locations from 29 patients with parkinsonism were connected to a brain network with the opposite spatial topography (spatial r=-0.85) compared to 347 patients with lesions causing seizures. A similar inverse relationship was found when comparing the connections that were most specific for lesions causing parkinsonism versus seizures on a group level (spatial r=-0.51) and on an individual lesion level (average spatial r=-0.042; p<0.001). The substantia nigra was found to be most positively correlated to the parkinsonism network but most negatively correlated to the seizure network (spatial r>0.8). Brain lesions causing parkinsonism versus seizures map to opposite brain networks, providing neuroanatomical insight into conflicting epidemiological evidence.
... Given that brain lesions can cause symptoms that are nearly identical to those observed in idiopathic dystonia, cases of lesion-induced dystonia are especially valuable because they allow for causal links between the damaged brain region/s and the resultant symptoms LeDoux & Brady, 2003). However, unlike other neurological symptoms, such as memory loss consistently being associated with lesions of the temporal lobe (Scoville & Milner, 1957), or parkinsonism most often associated with lesions of the nigrostriatal tract ( Joutsa, Horn, & Fox, 2018), lesions causing dystonia have been found in many regions throughout the brain (Kim et al., 2009;Munchau et al., 2000;O'Rourke, O'Riordan, Gallagher, & Hutchinson, 2006). This highlights the complexity of dystonia, strengthening suggestions of a 'network disorder', involving interactions between numerous structures ( Jinnah, Neychev, et al., 2017;Prudente, Hess, & Jinnah, 2014). ...
... In LNM, this wiring diagram is leveraged to find the connectivity from all brain lesions causing a given disorder, therefore evaluating whether each lesion is connected to common neural substrates. LNM has now been applied to a range of neurological and psychiatric disorders, such as parkinsonism (Joutsa et al., 2018), hallucinations (Kim et al., 2021), and mania (Cotovio et al., 2020), and recently to CD (Corp et al., 2019). ...
While dystonia has traditionally been viewed as a disorder of the basal ganglia, the involvement of other key brain structures is now accepted. However, just what these structures are remains to be defined. Neuroimaging has been an especially valuable tool in dystonia, yet traditional cross-sectional designs have not been able to separate causal from compensatory brain activity. Therefore, this chapter discusses recent studies using causal brain lesions, and animal models, to converge upon the brain regions responsible for dystonia with increasing precision. This evidence strongly implicates the basal ganglia, thalamus, brainstem, cerebellum, and somato- sensory cortex, yet shows that different types of dystonia involve different nodes of this brain network. Nearly all of these nodes fall within the recently identified two-way networks connecting the basal ganglia and cerebellum, suggesting dysfunction of these specific pathways. Localisation of the functional anatomy of dystonia has strong implications for targeted treatment options, such as deep brain stimulation, and non-invasive brain stimulation.
... 21,22 Both functional diaschisis and structural disconnection analyses have served to understand or predict several neuropsychological deficits and movement disorders secondary to stroke. 18,20,[23][24][25][26] Both methods have their individual advantages and shortcomings. First, they only provide indirect measures of diaschisis, although the validity of indirect measures of functional diaschisis has recently been demonstrated. ...
... Finally, our study had to rely on the original lesion maps drawn onto predefined slices of an MNI template, which were then expanded along the z-axis to create lesion volumes, rather than using the clinical images themselves. This is in line with lesion network mapping studies from other groups, 18,23,24,76,77 and it allowed us to compile the largest lesion dataset of patients with pusher syndrome to date, albeit with reduced spatial accuracy of the lesion maps. ...
The presence of both, isolated thalamic and isolated cortical lesions have been reported in the context with pusher syndrome - a disorder characterized by a disturbed perception of one's own upright body posture, following unilateral left- or right-sided stroke. In recent times, indirect quantification of functional and structural disconnection increases the knowledge derived from focal brain lesions by inferring subsequent brain network damage from the respective lesion. We applied both measures to a sample of 124 stroke patients to investigate brain disconnection in pusher syndrome. Our results suggest a hub-like function of the posterior and lateral portions of the thalamus in the perception of one's own postural upright. Lesion network-symptom-mapping investigating functional disconnection indicated cortical diaschisis in cerebellar, frontal, parietal, and temporal areas in patients with thalamic lesions suffering from pusher syndrome, but there was no evidence for functional diaschisis in pusher patients with cortical stroke and no evidence for the convergence of thalamic and cortical lesions onto a common functional network. Structural disconnection mapping identified posterior thalamic disconnection to temporal, pre-, post- and paracentral regions. Fibre tracking between the thalamic and cortical pusher lesion hotspots indicated that also in cortical lesions of patients with pusher syndrome it is disconnectivity to the posterior thalamus caused by accompanying white matter damage, rather than the direct cortical lesions themselves that lead to the emergence of pusher syndrome. Our analyses thus offer the first evidence for a direct thalamo-cortical (or cortico-thalamic) interconnection and, more importantly, shed light on the location of the respective thalamo-cortical disconnections. Pusher syndrome seems to be a consequence of direct damage or of disconnection of the posterior thalamus.
... Lesion masks were manually delineated in the MNI152 2 mm brain template in the same slices and orientations reported in the manuscripts. This method of lesion mapping has been widely used in lesion network mapping, and also in structural connectivity studies [131][132][133][134] . ...
Distinctive patterns of brain neurotransmission frame determinant circuits for behavior. Understanding the relationship between their damage and the cognitive impairment provoked by brain lesions could provide insights into the pathophysiology and therapeutics of disabling disorders, like stroke. Yet, the challenges of neurotransmitter circuits mapping in vivo have hampered this investigation. Here, we developed an MRI white matter atlas of neurotransmitter circuits and created a method to chart how stroke damages neurotransmitter systems, which distinguishes pre and postsynaptic disruption. Our model, trained and tested in two large stroke patient samples, identified eight clusters with different neurochemical patterns. The associations with patients’ cognitive profiles were scarce, denoting that a particular cognitive deficit might have finer underlying neurochemical disturbances that are unfit to the granularity of our analyses. These findings depict stroke neurochemical diaschisis patterns, provide insights into stroke cognitive deficits and potential treatments, and open a new window for tailored neurotransmitter modulation.
... In principle, if damage to a particular brain circuit causes a symptom, then it may be reasonable to hypothesize that stimulating the same circuit would relieve that symptom. Data consistent with this possibility have emerged for different disorders, including depression (12), anxiety (13), tremor (14), both motor and cognitive symptoms in Parkinson's disease (15,16), epilepsy (17), and vertigo (18). Across these disorders, lesions that incidentally cause a symptom map to a specific network, and TMS and/or deep brain stimulation (DBS) sites that incidentally target that network tend to modify that symptom. ...
Causal network mapping is an emerging technique that can be used to derive optimal disorder/symptom-specific brain stimulation targets. This technique exploits incidental variability in brain lesion and brain stimulation locations, which creates a natural experiment in which causal inferences can be drawn between lesions or modulation of specific circuits and specific clinical outcomes. Circuits identified by causal network mapping, referred to as symptom-networks, represent candidate disorder/symptom-specific brain stimulation targets. The number of psychiatric symptom-networks has grown rapidly in recent years, creating a need for a comprehensive synthesis. To address this gap, this Resource presents an atlas of 12 psychiatric symptom-network targets and appraises them using an established evaluative framework. We describe how these targets can be localized with and without neuroimaging and highlight key considerations surrounding their trialing and implementation. These materials are designed to spur the translation of symptom-network targets and scaffold advancements in this quickly developing field. 3
... Importantly, DBS targeting the subthalamic nucleus (STN) connects to claustral networks, correlating with clinical improvement. These findings suggest that the claustrum is a potential therapeutic node, where various parkinsonian syndromes may converge [135,136]. ...
Background: The mechanisms underlying extrapyramidal disorders and their anatomical substrate have been extensively investigated. Recently, the role of the claustrum in Parkinson’s disease and other neurodegenerative conditions has been better detailed. The main aim of this review was to summarize the supporting evidence for the role of the claustrum in degenerative and vascular parkinsonism. Methods: The anatomy, biology, vascular supply, and connections of the claustrum in humans were identified and described, providing the substrate for the vascular involvement of the claustrum in large- and small-vessel disease. The vascular supply of the claustrum includes up to three different sources from a single artery, the middle cerebral artery, and it is known as territory with an intermediate hemodynamic risk. The connections of the claustrum make it a sensory integrator and a relevant point in several networks, from consciousness to movement planning. Conclusions: The claustrum is still an incompletely explained structure. However, recent description of its multiple connections indicate that it is involved in several diseases, including Parkinson’s disease. The evidence underlying its potential role in vascular parkinsonism is still scarce, but it might be a field warranting future investigations.
... DBS, being an ideal, safe and reversible treatment for poststroke hemiplegia, holds immense potential for future advancements in stroke recovery therapies. 37 The mesencephalic locomotor region (MLR), situated at the pontomesencephalic junction between the substantia nigra and locus coeruleus, comprises diverse neuronal populations. Key cell types are GABA, glutamatergic and cholinergic neurons, structuring four subregions: pedunculopontine nucleus, rostrocaudal areas of pre-cuneiform and cuneiform nuclei (CnF), along with the adjacent mesencephalic reticular formation. ...
Introduction
Deep brain stimulation (DBS) and vagus nerve stimulation (VNS) can improve motor function in patients with poststroke hemiplegia. No comparison study exists.
Methods and analysis
This is a randomised, double-blind, controlled clinical trial involving 64 patients who had their first stroke at least 6 months ago and are experiencing poststroke limb dysfunction. These patients must receive necessary support at home and consent to participate. The aim is to evaluate the effectiveness and safety of DBS and VNS therapies. Patients are excluded if they have implantable devices that are sensitive to electrical currents, severe abnormalities in their lower limbs or are unable to comply with the trial procedures. The study has two parallel, distinct treatment arms: the Stimulation Group and the Sham Group. Initially, the Stimulation Group will undergo immediate electrical stimulation postsurgery, while the Sham Group will receive non-stimulation 1 month later. After 3 months, these groups will swap treatments, with the Stimulation Group discontinuing stimulation and the Sham Group initiating stimulation. Six months later, both groups will resume active stimulation. Our primary outcomes will meticulously assess motor function improvements, using the Fugl-Meyer Assessment, and safety, monitored by tracking adverse reaction rates. Furthermore, we will gain a comprehensive view of patient outcomes by evaluating secondary measures, including clinical improvement (National Institutes of Health Stroke Scale), surgical complications/side effects, quality of life (36-item Short Form Questionnaire) and mental health status (Hamilton Anxiety Rating Scale/Hamilton Depression Rating Scale). To ensure a thorough understanding of the long-term effects, we will conduct follow-ups at 9 and 12 months postsurgery, with additional long-term assessments at 15 and 18 months. These follow-ups will assess the sustained performance and durability of the treatment effects. The statistical analysis will uncover the optimal treatment strategy for poststroke hemiplegia, providing valuable insights for clinicians and patients alike.
Ethics and dissemination
This study was reviewed and approved by the Ethical Committee of Chinese PLA General Hospital (S2022-789-01). The findings will be submitted for publication in peer-reviewed journals with online accessibility, ensuring adherence to the conventional scientific publishing process while clarifying how the research outcomes will be disseminated and accessed.
Trial registration number
NCT06121947.
... It is evident that CL sits at the intersection of numerous simple loops with the cortex [5]. The function of CL is not fully elucidated, but it has been reported that CL may related to schizophrenia [6], epilepsy [4,7], consciousness [8,9], parkinsonism [10], and stress/anxiety [11]. In this report, we describe a case of pontocerebellar hypoplasia with congenital CL deficiency who survived into his sixth decade. ...
We describe the case of a 63-year-old man with pontocerebellar hypoplasia without the claustrum (CL). The patient had a history of cerebral palsy, intelligent disability, cerebellar atrophy, and seizures since birth. At age 61, brain computed tomography (CT) revealed significant cerebellar and brainstem atrophy. At age 63, he was admitted to our hospital for aspiration pneumonia. Although he was treated with medications, including antibiotics, he died one month after admission. The autopsy revealed a total brain weight of 815 g, with the small-sized frontal lobe, cerebellum, and pons. The cross-section of the fourth ventricle had a slit-like appearance, rather than the typical diamond shape. In addition, bilateral CLs were not observed. Apart from CL, no other missing brain tissue or cells could be identified. Microscopic examinations disclosed neurofibrillary tangles in the hippocampus but not in the cortex; however, neither senile plaques nor Lewy bodies were detected. No acquired lesions, including cerebral infarction, hemorrhage, or necrosis, were noted. We pathologically diagnosed the patient with pontocerebellar hypoplasia without CL. As there have been no prior reports of pontocerebellar hypoplasia lacking CL in adults, this case may represent a new subtype. Congenital CL deficiency is likely associated with abnormalities in brain development. CL may play a role in seizure activity, and the loss of bilateral CLs does not necessarily result in immediate death. Further studies are needed to clarify the functions of CL.
... Recently, an increasing number of studies have indicated that brain functions better localize to connected networks than to isolated brain regions [8][9][10] . For example, Using lesion network mapping (LNM) technique developed by our group 9 , we found that neurologic and psychiatric symptoms such as prosopagnosia 11 , amnesia 12 , movement disorders 13 , and a variety of other symptoms 9 correspond more closely to networks of connected regions than focal brain areas. In these studies, lesions that cause similar symptoms are located at different brain areas across patients but are part of the same network of connected regions. ...
Task functional magnetic resonance imaging research has generally shielded away from studying individuals due to the low reproducibility. Here, we propose that heterogeneous brain activations across individuals localize to a common network. To test this hypothesis, we use working memory (WM) as our example. First, we showed that discrete-brain-based reproducibility of brain activation during WM across individuals was low. Then, we used activation network mapping (ANM) technique to identify each individual’s brain network of WM and found that network-based reproducibility was rather high. Prediction analyses using machine learning algorithms indicated that individual WM networks identified via ANM can predict WM behavioral performance. This predictive ability even outperformed that of brain activations. Our study provides a new explanation on the low reproducibility of brain activations across individuals. The results suggest that ANM can be used to identify individual brain networks of cognitive processes, thus promising broad potential applications.
... 9 Recently, further networks involved in movement disorders such as parkinsonism and hemichorea have been identified using lesion network mapping. 11,12 This method assesses whole-brain connectivity from distributed lesions to investigate the network signature of specific neurological and psychiatric symptoms. 8 In this line, the specific distribution of brain lesions associated with the occurrence of DCP could be harnessed to delineate the neural network that underlies DCP. ...
Objective: Dyskinetic cerebral palsy (DCP) encompasses a group of predominantly perinatally acquired complex motor disorders that present with dystonia and/or choreoathetosis and are frequently associated with brain lesions in neuroimaging. Recently, lesion network mapping provided a tool to redefine neurological disorders as circuitopathies. In this study, we aim to assess lesion distribution in DCP and identify a DCP-related network derived from lesions.
Methods: Here, we review the literature of MRI findings in DCP and perform literature-based lesion network mapping (LNM). Imaging findings and their anatomical distribution were extracted from literature and quantified according to an established MRI classification system for cerebral palsy. Whole-brain functional connectivity from lesions causing DCP was calculated using a pediatric resting-state functional MRI connectome. Results were contrasted with two control datasets for spatial specificity.
Results: Review of 48 selected articles revealed that grey matter injury predominated (51%), followed by white matter injury (28%). In 16% of cases MRI was normal. Subcortical lesions affected the thalamus, pallidum and putamen in >40% of reported patients, respectively. Figures available from 23 literature cases were used to calculate DCP-LNM. The LNM revealed functional connectivity to a wide network including the brainstem, cerebellum, basal ganglia, cingulate, and sensorimotor cortices. Strongest connectivity was found for the motor thalamus.
Interpretation: The neural network of DCP identified with LNM includes areas previously implicated in hyperkinetic disorders and highlights the motor thalamus as a common network node. The effects of targeting motor thalamic networks with neuromodulation in DCP should be explored in future trials.
... The mesencephalic locomotor region (MLR) is critical for motor recovery (16)(17)(18)(19). The MLR ( Figure 1) is a phylogenetically conserved key motor control center in the brainstem, which is composed of two leading nuclei, namely the Pedunculopontine Nucleus (PPN) and the cuneate nucleus (CNF) (20)(21)(22)(23). PPN is associated with exploratory behavior, and deep brain stimulation (DBS) of PPN in patients with Parkinson's disease can reverse the freezing of gait (16,(23)(24)(25)(26)(27)(28). ...
Background
Deep brain stimulation (DBS) is a potential treatment for improving movement disorder. However, few large-sample studies can reveal its efficacy and safety. This study aims to initially explore the efficacy and safety of DBS in the mesencephalic locomotor region (MLR) on motor function in patients with post-stroke hemiplegia.
Methods/design
This multicenter, prospective, double-blind, randomized crossover clinical trial aims to assess the safety and effectiveness of Deep Brain Stimulation (DBS) in the mesencephalic locomotor region (MLR) for patients with moderate to severe post-stroke hemiplegia. Sixty-two patients with stable disease after a year of conservative treatment will be enrolled and implanted with deep brain electrodes. Post-surgery, patients will be randomly assigned to either the DBS group or the control group, with 31 patients in each. The DBS group will receive electrical stimulation 1 month later, while the control group will undergo sham stimulation. Stimulation will be discontinued after 3 and 6 months, followed by a 2-week washout period. Subsequently, the control group will receive electrical stimulation, while the DBS group will undergo sham stimulation. Both groups will resume electrical stimulation at the 9th and 12th-month follow-ups. Post-12-month follow-up, motor-related scores will be collected for analysis, with the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE) as the primary metric. Secondary outcomes include balance function, neuropsychiatric behavior, fall risk, daily living activities, and quality of life. This study aims to provide insights into the therapeutic benefits of DBS for post-stroke hemiplegia patients.
Result/conclusion
We proposed this study for the first time to comprehensively explore the effectiveness and safety of DBS in improving motor function for post-stroke hemiplegia, and provide evidence for DBS in the treatment of post-stroke hemiplegia. Study limitations are related to the small sample size and short study period.
Clinical Trial Registration
Clinicaltrials.gov, identifier NCT05968248.
... The observations have also been made in patients with PD themselves. Here, neuronal firing patterns recorded intraoperatively have shown higher rates of burst firing in the GPi and STN than equivalent firing patterns recorded in dystonic patients or non-human primates 14 non-human primate model 49,58,61,[68][69][70] , as well as within the tremor frequency (3-6 Hz) and beta band frequency (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) in PD patient recordings [71][72][73] . Moreover, at the neuronal population level, a substantial number of studies have demonstrated changes in oscillatory local field potential (LFP) components -recorded via DBS electrodesacross a series of spectral bands in the STN and GPi of patients with PD. ...
Bradykinesia, or slowness of movement, is a defining feature of Parkinson disease (PD) and a major contributor to the negative effects on quality of life associated with this disorder and related conditions. A dominant pathophysiological model of bradykinesia in PD has existed for approximately 30 years and has been the basis for the development of several therapeutic interventions, but accumulating evidence has made this model increasingly untenable. Although more recent models have been proposed, they also appear to be flawed. In this Perspective, I consider the leading prior models of bradykinesia in PD and argue that a more functionally related model is required, one that considers changes that disrupt the fundamental process of accurate information transmission. In doing so, I review emerging evidence of network level functional connectivity changes, information transfer dysfunction and potential motor code transmission error and present a novel model of bradykinesia in PD that incorporates this evidence. I hope that this model may reconcile inconsistencies in its predecessors and encourage further development of therapeutic interventions.
Link: https://rdcu.be/dL6vq
... An effective approach to analyse the network-level interactions is lesion network mapping (LNM), which helps identify the relationship between lesion locations causing specific symptoms and their connections to the rest of the brain by using normative resting-state fMRI data from healthy individuals. This method has previously been used to identify networks associated with various conditions such as tremor, tics and addictions [12][13][14][15] . ...
Thalamic aphasia results from focal thalamic lesions that cause dysfunction of remote but functionally connected cortical areas due to language network perturbation. However, specific local and network-level neural substrates of thalamic aphasia remain incompletely understood. Using lesion symptom mapping, we demonstrate that lesions in the left ventrolateral and ventral anterior thalamic nucleus are most strongly associated with aphasia in general and with impaired semantic and phonemic fluency and complex comprehension in particular. Lesion network mapping (using a normative connectome based on fMRI data from 1000 healthy individuals) reveals a Thalamic aphasia network encompassing widespread left-hemispheric cerebral connections, with Broca’s area showing the strongest associations, followed by the superior and middle frontal gyri, precentral and paracingulate gyri, and globus pallidus. Our results imply the critical involvement of the left ventrolateral and left ventral anterior thalamic nuclei in engaging left frontal cortical areas, especially Broca’s area, during language processing.
... Normative connectomes may also play a special role in understanding how spontaneously occurring focal insults (e.g., in the context of stroke) disrupt the normal organization of the brain 13 and how this may produce various symptoms. In particular, numerous studies have employed normative connectivity mapping to probe for distributed networks that may underpin post-stroke phenomena such as central pain 14 , parkinsonism 15 , and depression 16 . In each case, the connectome is typically 'seeded' using a region-of-interest (ROI), which represents the site of network perturbation, yielding a set of fiber streamlines (structural) or correlated brain areas (functional) that would tend to be impacted by this perturbation in the typical individual. ...
Diffusion-weighted MRI (dMRI) is a widely used neuroimaging modality that permits the in vivo exploration of white matter connections in the human brain. Normative structural connectomics – the application of large-scale, group-derived dMRI datasets to out-of-sample cohorts – have increasingly been leveraged to study the network correlates of focal brain interventions, insults, and other regions-of-interest (ROIs). Here, we provide a normative, whole-brain connectome in MNI space that enables researchers to interrogate fiber streamlines that are likely perturbed by given ROIs, even in the absence of subject-specific dMRI data. Assembled from multi-shell dMRI data of 985 healthy Human Connectome Project subjects using generalized Q-sampling imaging and multispectral normalization techniques, this connectome comprises ~12 million unique streamlines, the largest to date. It has already been utilized in at least 18 peer-reviewed publications, most frequently in the context of neuromodulatory interventions like deep brain stimulation and focused ultrasound. Now publicly available, this connectome will constitute a useful tool for understanding the wider impact of focal brain perturbations on white matter architecture going forward.
... Full details of the dataset and functional connectivity analyses have been published earlier (Joutsa et al., 2022b). The resulting connectivity maps were thresholded to |t| ≥ 7 to create lesion networks representing brain regions connected to lesion locations, as in prior work (Joutsa et al., 2018a). Finally, the lesion networks of the cases were overlapped to identify brain regions connected to lesion locations causing amusia. ...
Music is a universal human attribute. The study of amusia, a neurologic music processing deficit, has increasingly elaborated our view on the neural organization of the musical brain. However, lesions causing amusia occur in multiple brain locations and often also cause aphasia, leaving the distinct neural networks for amusia unclear. Here, we utilized lesion network mapping to identify these networks. A systematic literature search was carried out to identify all published case reports of lesion-induced amusia. The reproducibility and specificity of the identified amusia network were then tested in an independent prospective cohort of 97 stroke patients (46 female and 51 male) with repeated structural brain imaging, specifically assessed for both music perception and language abilities. Lesion locations in the case reports were heterogeneous but connected to common brain regions, including bilateral temporoparietal and insular cortices, precentral gyrus, and cingulum. In the prospective cohort, lesions causing amusia mapped to a common brain network, centering on the right superior temporal cortex and clearly distinct from the network causally associated with aphasia. Lesion-induced longitudinal structural effects in the amusia circuit were confirmed as reduction of both gray and white matter volume, which correlated with the severity of amusia. We demonstrate that despite the heterogeneity of lesion locations disrupting music processing, there is a common brain network that is distinct from the language network. These results provide evidence for the distinct neural substrate of music processing, differentiating music-related functions from language, providing a testable target for noninvasive brain stimulation to treat amusia.
... The brain structure most frequently affected by the ischemic lesion was the putamen in our cohort ( Figure S1). Moreover, in line with previously published studies [16,18] between PMD phenomenology and ischemic lesion site was recently proposed using a functional network-based rather than a structural approach to stroke localization [5,46], which may constitute a promising future study direction. The higher NIHSS score at discharge along with greater 3-month mRS and 6-month UPDRS II scores in the group who developed a PMD may suggest that patients with more clinically severe AIS are at higher risk for developing PMDs, although such results need to be confirmed in a larger population. ...
Background and purpose
Post‐stroke movement disorders (PMDs) following ischemic lesions of the basal ganglia (BG) are a known entity, but data regarding their incidence are lacking. Ischemic strokes secondary to proximal middle cerebral artery (MCA) occlusion treated with thrombectomy represent a model of selective damage to the BG. The aim of this study was to assess the prevalence and features of movement disorders after selective BG ischemia in patients with successfully reperfused acute ischemic stroke (AIS).
Methods
We enrolled 64 consecutive subjects with AIS due to proximal MCA occlusion treated with thrombectomy. Patients were clinically evaluated by a movement disorders specialist for PMDs onset at baseline, and after 6 and 12 months.
Results
None of the patients showed an identifiable movement disorder in the subacute phase of the stroke. At 6 and 12 months, respectively, 7/25 (28%) and 7/13 (53.8%) evaluated patients developed PMDs. The clinical spectrum of PMDs encompassed parkinsonism, dystonia and chorea, either isolated or combined. In most patients, symptoms were contralateral to the lesion, although a subset of patients presented with bilateral involvement and prominent axial signs.
Conclusion
Post‐stroke movement disorders are not uncommon in long‐term follow‐up of successfully reperfused AIS. Follow‐up conducted by a multidisciplinary team is strongly advisable in patients with selective lesions of the BG after AIS, even if asymptomatic at discharge.
... To avoid bias in control cohort selection, this data set included all other movement disorders on which our laboratory has performed lesion network mapping: Holmes tremor (n = 36), 26 cervical dystonia (n = 25), 24 tics (n = 19), and parkinsonism (n = 29). 27 Significance level was set at p < 0.05. ...
Background and objectives:
The cerebello-thalamo-cortical circuit plays a critical role in essential tremor (ET). However, abnormalities have been reported in multiple brain regions outside this circuit, leading to inconsistent characterization of ET pathophysiology. Here, we test whether these mixed findings in ET localize to a common functional network and if this network has therapeutic relevance.
Methods:
We conducted a systematic literature search to identify studies reporting structural or metabolic brain abnormalities in ET. We then employed 'coordinate network mapping', which leverages a normative connectome (n = 1000) of resting-state fMRI data to identify regions commonly connected to findings across all studies. To assess whether these regions may be relevant for treatment of ET, we compared our network to a therapeutic network derived from lesions that relieved ET. Finally, we investigated whether the functional connectivity of this ET symptom network is abnormal in an independent cohort of ET patients as compared to healthy controls.
Results:
Structural and metabolic brain abnormalities in ET were located in heterogeneous regions throughout the brain, but connected to a common functional network of brain regions, including the cerebellum, thalamus, motor cortex, precuneus, inferior parietal lobe and insula. The cerebellum was identified as the hub of this network as it was the only brain region that was both functionally connected to over 90% of studies' findings, and significantly different in connectivity compared to a control dataset of other movement disorders. This network was strikingly similar to the therapeutic network derived from lesions improving ET, with key regions aligning in the thalamus and cerebellum. Further, functional connectivity between the cerebellar network hub and the sensorimotor cortices was significantly reduced in ET patients compared to healthy controls, and connectivity within this network was correlated with tremor severity and cognitive functioning.
Discussion:
The cerebellum is the central hub of a network commonly connected to structural and metabolic abnormalities in ET. This network may have therapeutic utility in refining and informing new targets for neuromodulation of ET.
... Lesions causing depression were connected to the same network as TMS and DBS sites that preferentially modify depressionin other words, if a lesion to this network causes depression, then TMS to the same network is more likely to relieve depression than TMS to other networks [18]. At least five other studies have used lesion localization to identify optimal targets for either TMS or DBS for various disorders, including motor symptoms of Parkinson's disease [33], cognitive symptoms in Parkinson's disease [34], tic disorders [35], addiction [36], and tremor [37]. ...
The principle of targeting brain circuits has drawn increasing attention with the growth of brain stimulation treatments such as transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and focused ultrasound (FUS). Each of these techniques can effectively treat different neuropsychiatric disorders, but treating any given disorder depends on choosing the right treatment target. Here, we propose a three-phase framework for identifying and modulating these targets. There are multiple approaches to identifying a target, including correlative neuroimaging, retrospective optimization based on existing stimulation sites, and lesion localization. These techniques can then be optimized using personalized neuroimaging, physiological monitoring, and engagement of a specific brain state using pharmacological or psychological interventions. Finally, a specific stimulation modality or combination of modalities can be chosen after considering the advantages and tradeoffs of each. While there is preliminary literature to support different components of this framework, there are still many unanswered questions. This presents an opportunity for the future growth of research and clinical care in brain circuit therapeutics.
... 81 Both of these subcortical regions have been localized in previous meta-analyses of CBS, PSP and Parkinson's disease, 6,19,20 and as sites of lesions causing parkinsonism. [82][83][84][85] Further, although the inferior frontal and middle temporal gyri may not have established roles in the classical parkinsonian syndrome, both regions have been implicated in studies of individual disorders (e.g. in Parkinson's disease, PSP and MSA 48,86,87 ). These cortical regions have also been linked to behavioural inhibition 88 and freezing of gait, 89 respectively. ...
Parkinsonism is a feature of several neurodegenerative disorders, including Parkinson’s disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy. Neuroimaging studies have yielded insights into parkinsonian disorders; however, due to variability in results, the brain regions consistently implicated in these disorders remain to be characterized. The aim of this meta-analysis was to identify consistent brain abnormalities in individual parkinsonian disorders (Parkinson’s disease, progressive supranuclear palsy, corticobasal syndrome and multiple system atrophy) and to investigate any shared abnormalities across disorders. A total of 44 591 studies were systematically screened following searches of two databases. A series of whole-brain activation likelihood estimation meta-analyses were performed on 132 neuroimaging studies (69 Parkinson’s disease; 23 progressive supranuclear palsy; 17 corticobasal syndrome; and 23 multiple system atrophy) utilizing anatomical MRI, perfusion or metabolism PET and single-photon emission computed tomography. Meta-analyses were performed in each parkinsonian disorder within each imaging modality, as well as across all included disorders. Results in progressive supranuclear palsy and multiple system atrophy aligned with current imaging markers for diagnosis, encompassing the midbrain, and brainstem and putamen, respectively. PET imaging studies of patients with Parkinson’s disease most consistently reported abnormality of the middle temporal gyrus. No significant clusters were identified in corticobasal syndrome. When examining abnormalities shared across all four disorders, the caudate was consistently reported in MRI studies, whilst the thalamus, inferior frontal gyrus and middle temporal gyri were commonly implicated by PET. To our knowledge, this is the largest meta-analysis of neuroimaging studies in parkinsonian disorders and the first to characterize brain regions implicated across parkinsonian disorders.
... In each case, DBS sites that improve these symptoms are connected to the same brain circuit as lesions that caused these symptoms. [47][48][49] There remain important challenges for translating advances in lesion-based localization into therapeutic targets. First, there is no guarantee that lesions 'causing' a symptom will identify the best neuroanatomical target for 'improving' that symptom. ...
Historically, pathological brain lesions provided the foundation for localization of symptoms and therapeutic lesions were used as a treatment for brain diseases. New medications, functional neuroimaging and deep brain stimulation led to a decline in lesions in the past few decades. However, recent advances have improved our ability to localize lesion-induced symptoms, including localization to brain circuits rather than individual brain regions. Improved localization can lead to more precise treatment targets, which may mitigate traditional advantages of deep brain stimulation over lesions such as reversibility and tunability. New tools for creating therapeutic brain lesions such as high intensity focused ultrasound allow for lesions to be placed without a skin incision and are already in clinical use for tremor. Although there are limitations and caution is warranted, improvements in lesion-based localization are refining our therapeutic targets and improved technology is providing new ways to create therapeutic lesions, which together may facilitate the return of the lesion.
... In addition to strengthening causal inference, this cross-modality convergence also suggests that MS depression may respond to the same TMS targets as primary MDD and post-stroke depression, both of which are supported by multiple randomized clinical trials 23,24 . This is consistent with recent findings that lesion connectivity can help identify therapeutic targets for various neuropsychiatric disorders, including MDD 6 , Parkinson disease 6,25 and Tourette syndrome 26 . Future clinical trials should thus specifically investigate the antidepressant efficacy of TMS in people with MS, which has not yet been thoroughly studied 27 . ...
Multiple sclerosis (MS), a demyelinating disease that causes focal white matter lesions, is commonly associated with depression. However, it remains unclear whether depression risk is selectively increased by specific white matter lesion locations. Recent work shows that stroke lesions and therapeutic neuromodulation sites that modify depression severity are connected to a common brain circuit, providing an a priori template. Here we assessed whether this circuit is relevant for white matter lesions in MS. In a clinical and radiological database of individuals with MS (n = 281), we estimated the whole-brain connectivity of each person’s white matter lesion locations using a normative connectome database (n = 1,000). Functional connectivity between MS lesion locations and our a priori depression circuit was correlated with depression severity in MS (P = 0.013) and specific to depression versus other MS-related symptoms (P = 0.0058). A data-driven circuit for MS depression showed similar topography to our a priori depression circuit (P = 0.015). The peak of this data-driven MS depression circuit was in the ventral midbrain, including the ventral tegmental area (familywise-error-corrected P < 0.05). These findings lend insight into the localization of MS depression that may help guide targeting for therapeutic brain stimulation. Using lesion network mapping, Siddiqi, Kletenik et al. have identified a white matter lesion network for depression in people with multiple sclerosis.
... Finally, the new tools, namely Sweetspot, Fiber Filtering, and Network Mapping Explorer could be modified to map brain lesions associated with specific symptoms, corresponding to a form of voxel-based lesion mapping, disconnectome analysis and functional lesion network mapping analysis. While the Lead Mapper tool has already been used for functional lesion network mapping on multiple occasions (Darby et al., 2017;Ganos et al., 2022;Joutsa et al., 2018a), first reports have applied it for structural lesion network mapping, as well (Bowren et al., 2022;Trapp et al., 2022). ...
Following its introduction in 2014 and with support of a broad international community, the open-source toolbox Lead-DBS has evolved into a comprehensive neuroimaging platform dedicated to localizing, reconstructing, and visualizing electrodes implanted in the human brain, in the context of deep brain stimulation (DBS) and epilepsy monitoring. Expanding clinical indications for DBS, increasing availability of related research tools, and a growing community of clinician-scientist researchers, however, have led to an ongoing need to maintain, update, and standardize the codebase of Lead-DBS. Major development efforts of the platform in recent years have now yielded an end-to-end solution for DBS-based neuroimaging analysis allowing comprehensive image preprocessing, lead localization, stimulation volume modeling, and statistical analysis within a single tool. The aim of the present manuscript is to introduce fundamental additions to the Lead-DBS pipeline including a deformation warpfield editor and novel algorithms for electrode localization. Furthermore, we introduce a total of three comprehensive tools to map DBS effects to local, tract- and brain network-levels. These updates are demonstrated using a single patient example (for subject-level analysis), as well as a retrospective cohort of 51 Parkinson's disease patients who underwent DBS of the subthalamic nucleus (for group-level analysis). Their applicability is further demonstrated by comparing the various methodological choices and the amount of explained variance in clinical outcomes across analysis streams. Finally, based on an increasing need to standardize folder and file naming specifications across research groups in neuroscience, we introduce the brain imaging data structure (BIDS) derivative standard for Lead-DBS. Thus, this multi-institutional collaborative effort represents an important stage in the evolution of a comprehensive, open-source pipeline for DBS imaging and connectomics.
... Regardless of the cause of the lesion, its size or precise location, evidence has accumulated in recent years in favor of the connectome hypothesis whereby the specific network(s) affected by the lesion can predict many of the patient's responses through motor, non-motor, cognitive and behavioral domains 1-23 , leading to lesion-driven disconnectivity analyses 24 . A common computational framework was developed recently 2 , and successfully applied to several conditions and pathologies 3,4,6,7,[9][10][11][12][13][14][15][16][17][18]22,25 . Due to the simplicity of this method to correlate behavioral outcomes with the extent of lesion-driven disconnection, the strategy was referred to as lesion network mapping (LNM). ...
Beyond the characteristics of a brain lesion, such as its etiology, size or location, lesion network mapping (LNM) has shown that similar symptoms after a lesion reflects similar dis-connectivity patterns, thereby linking symptoms to brain networks. Here, we extend LNM by using a multimodal strategy, combining functional and structural networks from 1000 healthy participants in the Human Connectome Project. We apply multimodal LNM to a cohort of 54 stroke patients with the aim of predicting sensorimotor behavior, as assessed through a combination of motor and sensory tests. Results are two-fold. First, multimodal LNM reveals that the functional modality contributes more than the structural one in the prediction of sensorimotor behavior. Second, when looking at each modality individually, the performance of the structural networks strongly depended on whether sensorimotor performance was corrected for lesion size, thereby eliminating the effect that larger lesions generally produce more severe sensorimotor impairment. In contrast, functional networks provided similar performance regardless of whether or not the effect of lesion size was removed. Overall, these results support the extension of LNM to its multimodal form, highlighting the synergistic and additive nature of different types of network modalities, and their corresponding influence on behavioral performance after brain injury.
Causal network mapping is an emerging technique that can be used to derive optimal disorder/symptom-specific brain stimulation targets. This technique exploits incidental variability in brain lesion and brain stimulation locations, which creates a natural experiment in which causal inferences can be drawn between lesions or modulation of specific circuits and specific clinical outcomes. Circuits identified by causal network mapping, referred to as symptom-networks, represent candidate disorder/symptom-specific brain stimulation targets. The library of psychiatric symptom-networks has grown rapidly in recent years, creating a need for a comprehensive synthesis. The present Resource includes an open-source atlas of 12 psychiatric symptom-networks which we appraise using an established evaluative framework. These materials are designed to guide the translation of symptom-network targets and to scaffold advancements in this quickly developing field.
Claw horn disruption lesions (CHDL) are painful non-infectious foot lesions with significant animal welfare and socioeconomic impacts on the dairy industry. Lameness caused by CHDL is the main cause of involuntary culling, considerably reduces milk production, constitutes a major animal welfare concern and impacts directly on the sustainability of the sector through increased costs, veterinary intervention and raising replacement cattle with environmental implications. As a complex heritable polygenic disease, better understanding of the genomic architecture of CHDL pathogenesis and development is essential for facilitating genetic improvement of hoof health. Here we have performed in-depth genetic characterisation of ~ 3,000 cattle integrating multi-omic analyses: genome-wide association studies, whole genome sequencing, mRNA-sequencing, lncRNA-sequencing, expression quantitative trait loci analyses, reduced representation bisulfide sequencing, and multi-omics factor analysis (MOFA) in foot tissue and peripheral blood lymphocytes. Identified genetic variants and underlying pathways related to resistance to CHDL development elucidated new findings on underlying mechanisms including: complement cascade, inflammation, neuronal signalling (specifically perception of pain) and bone and cartilage development. This novel data could be applied to sustainably improve animal health and welfare as well as support the cattle sector.
Background and objectives: Ataxia is primarily considered to originate from the cerebellum. However, it can manifest without obvious cerebellar damage, such as in anterior circulation stroke, leaving the mechanisms of ataxia unclear. The aim of this study was to investigate whether stroke lesions causing limb ataxia localize to a common brain network.
Methods: In this prospective cohort study, adult patients with new-onset stroke with visible lesions on CT or MRI from Turku University Hospital, Finland, were clinically examined (1) after their stroke while still admitted to the hospital (baseline) and (2) 4 months later (follow-up) to assess limb ataxia. Lesion locations and their functional connectivity, computed using openly available data from 1,000 healthy volunteers from the Brain Genome Superstruct Project, were compared voxel-by-voxel across the whole brain between patients with and without ataxia, using voxel-based lesion-symptom mapping and lesion network mapping. The findings were confirmed in an independent stroke patient cohort with identical clinical assessments.
Results: One hundred ninety-seven patients (mean age 67.2 years, 39%female) were included in this study. At baseline, 35 patients (68.3 years, 34%female) had and 162 (67.0 years, 40%female) did not have new-onset acute limb ataxia. At follow-up, additional 4 patients had developed late-onset limb ataxia, totalling to 39 patients (68.6 years, 36%female) with limb ataxia at any point. One hundred eighteen patients (66.2 years, 40%female) did not have ataxia at any point (n = 40 with missing follow-up data). Lesions in 54% of the patients with acute limb ataxia were located outside the cerebellum and cerebellar peduncles, and we did not find an association between specific lesion locations and ataxia. Lesions causing acute limb ataxia, however, were connected to a common network centered on the intermediate zone cerebellum and cerebellar peduncles (lesion connectivity in patients with vs without acute limb ataxia, pFWE < 0.05). The results were similar when comparing patients with and without ataxia at any point, and when excluding lesions in the cerebellum and cerebellar peduncles (pFWE < 0.05). The findings were confirmed in the independent stroke dataset (n = 96), demonstrating an OR of 2.27 (95% CI 1.32-3.91) for limb ataxia per standard deviation increase in limb ataxia network damage score.
Discussion: Lesions causing limb ataxia occur in heterogeneous locations but localize to a common brain network.
A woman in her 70s presented with approximately 2 years of sudden-onset gait and cognitive problems. She had been diagnosed with normal pressure hydrocephalus (NPH) and underwent ventriculoperitoneal shunt (VPS) placement 1 year prior. Before VPS placement, brain imaging showed ventriculomegaly and chronic infarction of the right putamen and claustrum. A lumbar drain trial resulted in modest improvement of gait dysfunction. She underwent VPS placement for suspected NPH, but her symptoms remained unchanged. Examination revealed mild cognitive impairment, left-sided and lower body predominant parkinsonism, as well as disproportionately prominent postural instability. Gait analysis showed increased gait variability, reduced velocity and shortened step length bilaterally. Motor and gait abnormalities did not change after administration of levodopa. Her symptoms have remained stable for up to 52 months since symptom onset. We postulate that the infarction affecting the right putamen and claustrum could have led to a higher-level gait disorder mimicking NPH.
Recent epidemiological studies propose an association between parkinsonism and seizures, but the direction of this association is unclear. Focal brain lesions causing new-onset parkinsonism versus seizures may provide a unique perspective on the causal relationship between the two symptoms and involved brain networks. We studied lesions causing parkinsonism versus lesions causing seizures and used the human connectome to identify their connected brain networks. Brain networks for parkinsonism and seizures were compared using spatial correlations on a group and individual lesion level. Lesions not associated with either symptom were used as controls. Lesion locations from 29 patients with parkinsonism were connected to a brain network with the opposite spatial topography (spatial r = -0.85) compared to 347 patients with lesions causing seizures. A similar inverse relationship was found when comparing the connections that were most specific on a group level (spatial r = -0.51) and on an individual lesion level (average spatial r = -0.042; p<0.001). The substantia nigra was found to be most positively correlated to the parkinsonism network but most negatively correlated to the seizure network (spatial r>0.8). Brain lesions causing parkinsonism versus seizures map to opposite brain networks, providing neuroanatomical insight into conflicting epidemiological evidence.
Background
Alzheimer's disease (AD) is a prevalent neurodegenerative condition among the elderly population and the most common form of dementia, however, we lack potent interventions to arrest its inherent pathogenic vectors. Robust evidence indicates thermoregulatory perturbations during and before the onset of symptoms. Therefore, temperature-regulated biomarkers may offer clues to therapeutic targets during the presymptomatic stage.
Objective
The purpose of this study is to develop and assess a thermoregulation-related gene prediction model for Alzheimer's Disease diagnosis.
Method
This study aims to utilize microarray bioinformatic analysis to identify the potential biomarkers of AD by analyzing four microarray datasets (GSE48350, GSE5281, GSE122063, and GSE181279) of AD patients. Furthermore, thermoregulation-associated hub genes were identified, and the expression patterns in the brain were explored. In addition, we explored the infiltration of immune cells with thermoregulation-related hub genes. Diagnostic marker validation was then performed at the single-cell level. Finally, the prediction of targeted drugs was performed based on the hub genes.
Results
Through the analysis of four datasets pertaining to AD, a total of five genes associated with temperature regulation were identified. Notably, CCK, CXCR4, SLC27A4, and SLC17A6 emerged as diagnostic markers indicative of AD-related brain injury. Furthermore, in the examination of peripheral blood samples from AD patients, SLC27A4 and CXCR4 were identified as pivotal diagnostic indicators. Regrettably, animal experimentation was not pursued to validate the data; rather, an assessment of temperature regulation-related genes was conducted. Future investigations will be undertaken to establish the correlation between these genes and AD pathology.
Conclusion
Overall, CCK, CXCR4, SLC27A4, and SLC17A6 can be considered pivotal biomarkers for diagnosing the pathogenesis and molecular functions of AD.
Background and Hypothesis
Neuroimaging studies investigating the neural substrates of auditory verbal hallucinations (AVH) in schizophrenia have yielded mixed results, which may be reconciled by network localization. We sought to examine whether AVH-state and AVH-trait brain alterations in schizophrenia localize to common or distinct networks.
Study Design
We initially identified AVH-state and AVH-trait brain alterations in schizophrenia reported in 48 previous studies. By integrating these affected brain locations with large-scale discovery and validation resting-state functional magnetic resonance imaging datasets, we then leveraged novel functional connectivity network mapping to construct AVH-state and AVH-trait dysfunctional networks.
Study Results
The neuroanatomically heterogeneous AVH-state and AVH-trait brain alterations in schizophrenia localized to distinct and specific networks. The AVH-state dysfunctional network comprised a broadly distributed set of brain regions mainly involving the auditory, salience, basal ganglia, language, and sensorimotor networks. Contrastingly, the AVH-trait dysfunctional network manifested as a pattern of circumscribed brain regions principally implicating the caudate and inferior frontal gyrus. Additionally, the AVH-state dysfunctional network aligned with the neuromodulation targets for effective treatment of AVH, indicating possible clinical relevance.
Conclusions
Apart from unifying the seemingly irreproducible neuroimaging results across prior AVH studies, our findings suggest different neural mechanisms underlying AVH state and trait in schizophrenia from a network perspective and more broadly may inform future neuromodulation treatment for AVH.
There is disagreement regarding the major components of the brain network supporting spatial cognition. To address this issue, we applied a lesion mapping approach to the clinical phenomenon of topographical disorientation. Topographical disorientation is the inability to maintain accurate knowledge about the physical environment and use it for navigation. A review of published topographical disorientation cases identified 65 different lesion sites. Our lesion mapping analysis yielded a topographical disorientation brain map encompassing the classic regions of the navigation network: medial parietal, medial temporal and temporo-parietal cortices. We also identified a ventromedial region of the prefrontal cortex, which has been absent from prior descriptions of this network. Moreover, we revealed that the regions 3 mapped are correlated with the Default Mode Network sub-network C. Taken together, this study provides causal evidence for the distribution of the spatial cognitive system, demarking the major components and identifying novel regions. Running title: Lesion-based spatial orientation network
Background
The traditional approach to studying the neurobiological mechanisms of brain disorders and localizing brain function involves identifying brain abnormalities and comparing them to matched controls. This method has been instrumental in clinical neurology, providing insight into the functional roles of different brain regions. However, it becomes challenging when lesions in diverse regions produce similar symptoms. To address this, researchers have begun mapping brain lesions to functional or structural networks, a process known as lesion network mapping (LNM). This approach seeks to identify common brain circuits associated with lesions in various areas. In this review, we focus on recent studies that have utilized LNM to map neurological and psychiatric symptoms, shedding light on how this method enhances our understanding of brain network functions.
Methods
We conducted a systematic search of four databases: PubMed, Scopus, and Web of Science, using the term “Lesion network mapping.” Our focus was on observational studies that applied lesion network mapping in the context of neurological and psychiatric disorders.
Results
Following our screening process, we included 52 studies, comprising a total of 6,814 subjects, in our systematic review. These studies, which utilized functional connectivity, revealed several regions and network overlaps across various movement and psychiatric disorders. For instance, the cerebellum was found to be part of a common network for conditions such as essential tremor relief, parkinsonism, Holmes tremor, freezing of gait, cervical dystonia, infantile spasms, and tics. Additionally, the thalamus was identified as part of a common network for essential tremor relief, Holmes tremor, and executive function deficits. The dorsal attention network was significantly associated with fall risk in elderly individuals and parkinsonism.
Conclusion
LNM has proven to be a powerful tool in localizing a broad range of neuropsychiatric, behavioral, and movement disorders. It holds promise in identifying new treatment targets through symptom mapping. Nonetheless, the validity of these approaches should be confirmed by more comprehensive prospective studies.
Tics are sudden stereotyped movements or vocalizations. Cases of lesion-induced tics are invaluable, allowing for causal links between symptoms and brain structures. While a lesion network for tics has recently been identified, the degree to which this network translates to Tourette syndrome has not been fully elucidated. This is important given that patients with Tourette syndrome make up a large portion of tic cases, therefore existing and future treatments should apply to these patients. The aim of this study was to first localize a causal network for tics from lesion-induced cases and then refine and validate this network in patients with Tourette syndrome. We independently performed ‘lesion network mapping’ using a large normative functional connectome (n = 1000) to isolate a brain network commonly connected to lesions causing tics (n = 19) identified through a systematic search. The specificity of this network to tics was assessed through comparison to lesions causing other movement disorders. Using structural brain coordinates from prior neuroimaging studies (n = 7), we then derived a neural network for Tourette syndrome. This was done using standard anatomical likelihood estimation meta-analysis and a novel method termed ‘coordinate network mapping’, which uses the same coordinates, yet maps their connectivity using the aforementioned functional connectome. Conjunction analysis was used to refine the network for lesion-induced tics to Tourette syndrome by identifying regions common to both lesion and structural networks. We then tested whether connectivity from this common network is abnormal in a separate resting-state functional connectivity MRI dataset from idiopathic Tourette syndrome patients (n = 21) and healthy controls (n = 25). Results showed that lesions causing tics were distributed throughout the brain, however, consistent with a recent study, these were part of a common network with predominant basal ganglia connectivity. Using conjunction analysis, coordinate network mapping findings refined the lesion network to the posterior putamen, caudate nucleus, globus pallidus externus (positive connectivity), and precuneus (negative connectivity). Functional connectivity from this positive network to frontal and cingulate regions was abnormal in patients with idiopathic Tourette syndrome. These findings identify a network derived from lesion-induced and idiopathic data, providing insight into the pathophysiology of tics in Tourette syndrome. Connectivity to our cortical cluster in the precuneus offers an exciting opportunity for non-invasive brain stimulation protocols.
Vertigo is a common neurological complaint, which can result in significant morbidity and decreased quality of life. While pathology to peripheral and subtentorial brain structures is a well-established cause of vertigo, cortical lesions have also been linked to vertigo and may lend insight into relevant neuroanatomy. Here, we investigate the supratentorial lesion locations associated with vertigo and test whether they map to a common brain network. We performed a systematic literature search and identified 23 cases of supratentorial brain lesions associated with vertigo. We mapped the lesion locations to a standard brain template and computed the network of brain regions functionally connected to each lesion location, using a ‘wiring diagram’ of the human brain termed the human connectome (n = 1000). Sensitivity was assessed by identifying the most common connection to lesion locations associated with vertigo, and specificity was assessed through comparison with control lesions associated with symptoms other than vertigo (n = 68). We found that functional connectivity between lesion locations and the bilateral ventral posterior insula was both sensitive (22/23 lesions) and specific (voxel-wise family-wise error -corrected P < 0.05) for lesion-induced vertigo. We computed connectivity with this hub region to define a lesion-based vertigo network, which included regions in the bilateral insula, somatosensory cortex, higher-level visual areas, cingulate sulcus, thalamus, and multiple cerebellar regions in the territory of the posterior inferior cerebellar artery. Next, we used stereo-electroencephalography (80 stimulation sites across 17 patients) to test whether stimulation sites associated with vertigo mapped to this same network. We found that 36/42 (86%) of stimulation sites eliciting vertigo fell within the lesion-based vertigo network in contrast to 16/39 (41%) of stimulation sites that did not elicit vertigo. Connectivity between stimulation sites and our lesion-based hub in the ventral posterior insula was also significantly associated with vertigo (P < 0.0001). We conclude that cortical lesions and direct electrical stimulation sites associated with vertigo map to a common brain network, offering insights into the causal neuroanatomical substrate of vertigo.
We mapped the distribution of atrophy in Parkinson's disease (PD) using magnetic resonance imaging (MRI) and clinical data from 232 PD patients and 117 controls from the Parkinson's Progression Markers Initiative. Deformation-based morphometry and independent component analysis identified PD-specific atrophy in the midbrain, basal ganglia, basal forebrain, medial temporal lobe, and discrete cortical regions. The degree of atrophy reflected clinical measures of disease severity. The spatial pattern of atrophy demonstrated overlap with intrinsic networks present in healthy brain, as derived from functional MRI. Moreover, the degree of atrophy in each brain region reflected its functional and anatomical proximity to a presumed disease epicenter in the substantia nigra, compatible with a trans-neuronal spread of the disease. These results support a network-spread mechanism in PD. Finally, the atrophy pattern in PD was also seen in healthy aging, where it also correlated with the loss of striatal dopaminergic innervation.
Background
Patients with brain lesions provide a unique opportunity to understand the functioning of the human mind. However, even when focal, brain lesions have local and remote effects that impact functionally and structurally connected circuits. Similarly, function emerges from the interaction between brain areas rather than their sole activity. For instance, category fluency requires the association between executive, semantic and language production functions.
Findings
Here we provide, for the first time, a set of complementary solutions to measure the impact of a given lesion upon the neuronal circuits. Our methods, which were applied to 37 patients with a focal frontal brain lesion, revealed a large set of directly and indirectly disconnected brain regions that had significantly impacted category fluency performance. The directly disconnected regions corresponded to areas that are classically considered as functionally engaged in verbal fluency and categorization tasks. These regions were also organized into larger directly and indirectly disconnected functional networks, including the left ventral fronto-parietal network, whose cortical thickness correlated with performance on category fluency.
Conclusions
The combination of structural and functional connectivity together with cortical thickness estimates reveals the remote effects of brain lesions, provide for the identification of the affected networks and strengthen our understanding of their relationship with cognitive and behavioural measures. The methods presented are available and freely accessible in the BCBtoolkit as supplementary software [1].
In Europe, more than 2 million individuals each year will have their brain integrity and function challenged by stroke. Despite the progress achieved through the use of thrombolysis with alteplase in acute stroke patients (Wahlgren et al., 2007), many have persistent deficits, affecting their personality, degrading their quality of life and preventing their return to work. Patients need to know, in a timely manner, to what extent their symptoms will resolve. This knowledge reduces the burden and stress associated with stroke, and allows patients to make appropriate arrangements with their family, their health insurance provider and their employer. The mechanics of recovery...
Significance
Functional MRI has been widely used to assess the functional architecture of the brain based on detecting changes in neural activity in gray matter via blood oxygenation level-dependent (BOLD) effects. However, the existence and possible relevance of BOLD signals in white matter remain controversial. We demonstrate that BOLD signals in functional cortical volumes are strongly correlated with signals in specific, segmented white matter tracts in a resting state, and the correlations can be modulated by specific functional loadings. We therefore show that current concepts of functional connectivity based on synchronous BOLD correlations may be extended to include white matter and that changes in neural activity are encoded in BOLD variations throughout the brain.
To identify progressive supranuclear palsy (PSP), we combined voxel-based morphometry (VBM) and support vector machine (SVM) classification using disease-specific features in multicentric magnetic resonance imaging (MRI) data. Structural brain differences were investigated at four centers between 20 patients with PSP and 20 age-matched healthy controls with T1-weighted MRI at 3T. To pave the way for future application in personalized medicine, we applied SVM classification to identify PSP on an individual level besides group analyses based on VBM. We found a major decline in gray matter density in the brainstem, insula, and striatum, and also in frontomedian regions, which is in line with current literature. Moreover, SVM classification yielded high accuracy rates above 80% for disease identification in imaging data. Focusing analyses on disease-specific regions-of-interest (ROI) led to higher accuracy rates compared to a whole-brain approach. Using a polynomial kernel (instead of a linear kernel) led to an increased sensitivity and a higher specificity of disease detection. Our study supports the application of MRI for individual diagnosis of PSP, if combined with SVM approaches. We demonstrate that SVM classification provides high accuracy rates in multicentric data—a prerequisite for potential application in diagnostic routine.
On the 50th anniversary of Norman Geschwind's seminal paper entitled 'Disconnexion syndrome in animal and man', we pay tribute to his ideas by applying contemporary tractography methods to understand white matter disconnection in 3 classic cases that made history in behavioral neurology. We first documented the locus and extent of the brain lesion from the computerized tomography of Phineas Gage's skull and the magnetic resonance images of Louis Victor Leborgne's brain, Broca's first patient, and Henry Gustave Molaison. We then applied the reconstructed lesions to an atlas of white matter connections obtained from diffusion tractography of 129 healthy adults. Our results showed that in all 3 patients, disruption extended to connections projecting to areas distant from the lesion. We confirmed that the damaged tracts link areas that in contemporary neuroscience are considered functionally engaged for tasks related to emotion and decision-making (Gage), language production (Leborgne), and declarative memory (Molaison). Our findings suggest that even historic cases should be reappraised within a disconnection framework whose principles were plainly established by the associationist schools in the last 2 centuries.
© The Author 2015. Published by Oxford University Press.
A traditional and widely used approach for linking neurological symptoms to specific brain regions involves identifying overlap in lesion location across patients with similar symptoms, termed lesion mapping. This approach is powerful and broadly applicable, but has limitations when symptoms do not localize to a single region or stem from dysfunction in regions connected to the lesion site rather than the site itself. A newer approach sensitive to such network effects involves functional neuroimaging of patients, but this requires specialized brain scans beyond routine clinical data, making it less versatile and difficult to apply when symptoms are rare or transient. In this article we show that the traditional approach to lesion mapping can be expanded to incorporate network effects into symptom localization without the need for specialized neuroimaging of patients. Our approach involves three steps: (i) transferring the three-dimensional volume of a brain lesion onto a reference brain; (ii) assessing the intrinsic functional connectivity of the lesion volume with the rest of the brain using normative connectome data; and (iii) overlapping lesion-associated networks to identify regions common to a clinical syndrome. We first tested our approach in peduncular hallucinosis, a syndrome of visual hallucinations following subcortical lesions long hypothesized to be due to network effects on extrastriate visual cortex. While the lesions themselves were heterogeneously distributed with little overlap in lesion location, 22 of 23 lesions were negatively correlated with extrastriate visual cortex. This network overlap was specific compared to other subcortical lesions (P < 10(-5)) and relative to other cortical regions (P < 0.01). Next, we tested for generalizability of our technique by applying it to three additional lesion syndromes: central post-stroke pain, auditory hallucinosis, and subcortical aphasia. In each syndrome, heterogeneous lesions that themselves had little overlap showed significant network overlap in cortical areas previously implicated in symptom expression (P < 10(-4)). These results suggest that (i) heterogeneous lesions producing similar symptoms share functional connectivity to specific brain regions involved in symptom expression; and (ii) publically available human connectome data can be used to incorporate these network effects into traditional lesion mapping approaches. Because the current technique requires no specialized imaging of patients it may prove a versatile and broadly applicable approach for localizing neurological symptoms in the setting of brain lesions.
© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
The goal of the Brain Genomics Superstruct Project (GSP) is to enable large-scale exploration of the links between brain function, behavior, and ultimately genetic variation. To provide the broader scientific community data to probe these associations, a repository of structural and functional magnetic resonance imaging (MRI) scans linked to genetic information was constructed from a sample of healthy individuals. The initial release, detailed in the present manuscript, encompasses quality screened cross-sectional data from 1,570 participants ages 18 to 35 years who were scanned with MRI and completed demographic and health questionnaires. Personality and cognitive measures were obtained on a subset of participants. Each dataset contains a T1-weighted structural MRI scan and either one (n=1,570) or two (n=1,139) resting state functional MRI scans. Test-retest reliability datasets are included from 69 participants scanned within six months of their initial visit. For the majority of participants self-report behavioral and cognitive measures are included (n=926 and n=892 respectively). Analyses of data quality, structure, function, personality, and cognition are presented to demonstrate the dataset's utility.
The claustrum is a mysterious thin sheet of neurons lying between the insular cortex and the striatum. It is reciprocally connected with almost all cortical areas, including motor, somatosensory, visual, auditory, limbic, associative, and prefrontal cortices. In addition, it receives neuromodulatory input from subcortical structures. A decade ago, Sir Francis Crick and Christof Koch published an influential review proposing the claustrum as the 'seat of consciousness', spurring a revival of interest in the claustrum. We review the literature on the claustrum, emphasizing recent discoveries, and develop a detailed hypothesis describing a role for the claustrum in the segregation of attention.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Background and PurposeAccurate diagnosis of Atypical Parkinsonian Syndromes (APS) is important due to differences in prognosis and management, but remains a challenge in the clinical setting. The purpose of our meta-analysis was to identify characteristic patterns of gray matter atrophy in Corticobasal Degeneration (CBD), Progressive Supranuclear Palsy (PSP), Multisystem-Atrophy Parkinsonian type (MSA-P), and Idiopathic Parkinson's Disease (IPD).Materials and Methods
Whole-brain meta-analysis was performed on 39 published voxel-based morphometry (VBM) articles (consisting of 404 IPD, 87 MSA-P, 165 CBD, and 176 PSP subjects) using the modified Anatomic Likelihood Estimation method. Based on these results, contrast analyses were then utilized to determine areas of atrophy shared by as well as unique to each disorder.ResultsCBD was characterized by asymmetric gray matter atrophy in multiple cortical regions, while the thalamus-midbrain and insula were predominantly involved in PSP. The striatum and superior cerebellum were affected in MSA-P, while IPD demonstrated an anterior cerebral pattern. Although there was a mild overlap among PSP, CBD, and MSA-P, significant regions of atrophy unique to each disorder were identified, including (1) the superior parietal lobule in CBD (2) putamen in MSA-P (3) insula and medial dorsal nucleus in PSP.Conclusion
Our results suggest that there are characteristic patterns of atrophy in APS. Guided by these findings, future studies on the individual subject level may lead to the development of robust imaging biomarkers.
A long-held view is that stroke causes many distinct neurological syndromes due to damage of specialized cortical and subcortical centers. However, it is unknown if a syndrome-based description is helpful in characterizing behavioral deficits across a large number of patients. We studied a large prospective sample of first-time stroke patients with heterogeneous lesions at 1-2 weeks post-stroke. We measured behavior over multiple domains and lesion anatomy with structural MRI and a probabilistic atlas of white matter pathways. Multivariate methods estimated the percentage of behavioral variance explained by structural damage. A few clusters of behavioral deficits spanning multiple functions explained neurological impairment. Stroke topography was predominantly subcortical, and disconnection of white matter tracts critically contributed to behavioral deficits and their correlation. The locus of damage explained more variance for motor and language than memory or attention deficits. Our findings highlight the need for better models of white matter damage on cognition.
Copyright © 2015 Elsevier Inc. All rights reserved.
Significance
Brain stimulation is a powerful treatment for an increasing number of psychiatric and neurological diseases, but it is unclear why certain stimulation sites work or where in the brain is the best place to stimulate to treat a given patient or disease. We found that although different types of brain stimulation are applied in different locations, targets used to treat the same disease most often are nodes in the same brain network. These results suggest that brain networks might be used to understand why brain stimulation works and to improve therapy by identifying the best places to stimulate the brain.
To compare the clinical and imaging characteristics of those PRECEPT (Parkinson Research Examination of CEP-1347 Trial) subjects with a scan without evidence of dopaminergic deficit (SWEDD) to those with dopamine transporter (DAT) deficit scans at study baseline and during a 22-month follow-up.
Baseline (n = 799) and 22-month follow-up (n = 701) [(123)I] β-CIT SPECT scans were acquired. The percent change in [(123)I] β-CIT striatal binding ratio, the percentage of subjects requiring dopaminergic therapy, the change in Unified Parkinson's Disease Rating Scale (UPDRS) score, and the PRECEPT Study investigators' diagnosis at study termination were compared between SWEDD and DAT deficit subjects.
SWEDD subjects (n = 91) compared with DAT deficit subjects (n = 708) showed reduced UPDRS score at baseline (18.7 [SD 8.5] vs 25.5 [SD 10.5], p < 0.05) and minimal change in both [(123)I] β-CIT striatal binding ratio (-0.2% [SD 12.2] vs -8.5% [SD 11.9], p < 0.0001) and UPDRS score (0.5 [SD 6.9] vs 10.5 [SD 8.9], p < 0.0001) at follow-up assessments. At PRECEPT termination, the diagnosis by study investigators was changed from Parkinson disease (PD) to other disorders not associated with DAT deficit in 44% (95% confidence interval 34.2, 54.7) of SWEDD subjects compared with 3.6% (95% confidence interval 2.3, 5.1) of DAT deficit subjects.
These results indicate that subjects identified as having a SWEDD, with DAT imaging within the normal range, have minimal evidence of clinical or imaging PD progression. These data strongly suggest that SWEDD subjects are unlikely to have idiopathic PD.
Purpose:
Pallidoreticular damage was defined by lesions involving both the pallidum and the substantia nigra and was only reported in four cases after CO intoxication.
Case report:
We report a patient with initial consciousness disturbances followed by parkinsonian features after carbon monoxide intoxication. The unique features in this patient included primary globus pallidus hemorrhage followed by delayed hemorrhage in pallidoreticular topography demonstrated by T1- and T2-weighted imaging. In the follow-up study 7 months later, the patient still presented with parkinsonism features and executive dysfunction while the pallidoreticular signal was only visible by gradient echo sequences but not the other MR conventional sequences. Hypometabolism in the frontal and basal ganglion regions were evident from 99mTc-TRODAT-1 study and partial responsiveness to levodopa in alleviating parkinsonian features was considered.
Conclusion:
This case highlights the delayed development of pallidoreticular damages and its linkage in modulating prefrontal-subcortical neuronal circuits.
Bilateral ischemic infarction involving the corpus striatum is a rare event which usually results from global cerebral hypoxia, intoxications, and drug abuse.
We report a 28 year old Caucasian woman who presented with progressive obtundation and later development of severe expressive dysphasia and Parkinsonism after sustaining ischemic stroke of both corpora striata. Hemorrhagic transformation developed on day four of admission.
This is a rare case of bilateral basal ganglia infarction with hemorrhagic transformation in a young patient. Our patient's work up did not reveal any cause behind this stroke; however, advanced investigations (such as genetic testing and conventional angiography) were not done. The damage resulted in motor dysphasia and Parkinsonism. Neither dystonia nor other involuntary movements developed, and cognitive function was not assessed because of the language disorder.
Information processing in the cerebral cortex involves interactions among distributed areas. Anatomical connectivity suggests that certain areas form local hierarchical relations such as within the visual system. Other connectivity patterns, particularly among association areas, suggest the presence of large-scale circuits without clear hierarchical relations. In this study the organization of networks in the human cerebrum was explored using resting-state functional connectivity MRI. Data from 1,000 subjects were registered using surface-based alignment. A clustering approach was employed to identify and replicate networks of functionally coupled regions across the cerebral cortex. The results revealed local networks confined to sensory and motor cortices as well as distributed networks of association regions. Within the sensory and motor cortices, functional connectivity followed topographic representations across adjacent areas. In association cortex, the connectivity patterns often showed abrupt transitions between network boundaries. Focused analyses were performed to better understand properties of network connectivity. A canonical sensory-motor pathway involving primary visual area, putative middle temporal area complex (MT+), lateral intraparietal area, and frontal eye field was analyzed to explore how interactions might arise within and between networks. Results showed that adjacent regions of the MT+ complex demonstrate differential connectivity consistent with a hierarchical pathway that spans networks. The functional connectivity of parietal and prefrontal association cortices was next explored. Distinct connectivity profiles of neighboring regions suggest they participate in distributed networks that, while showing evidence for interactions, are embedded within largely parallel, interdigitated circuits. We conclude by discussing the organization of these large-scale cerebral networks in relation to monkey anatomy and their potential evolutionary expansion in humans to support cognition.
Bilateral anterior cerebral artery (ACA) territory infarction is rare and its associated symptoms are still not well understood. We evaluated the clinical symptoms of four patients with bilateral ACA infarction. The common clinical features were various primitive reflexes and parkinsonian symptoms including akinesia, rigidity and hypophonia. Frontal release signs were present in all patients with ACA infarction even without direct involvement of the prefrontal cortex. Enhanced glabellar tap response, previously not reported in patients with ACA infarction, was the most consistent finding, and electrophysiological studies confirmed hyperexcitability of the late component of the blink reflex. The bilateral lesions in the deep white matter may be associated with the observed symptoms, reflecting functional disconnection of the medial prefrontal-subcortical circuitry.
Many different types of hyperkinetic and hypokinetic movement disorders have been reported after ischaemic and haemorrhagic
stroke. We searched the Medline database from 1966 to February 2008, retrieving 2942 articles from which 156 relevant case
reports, case series and review articles were identified. The papers were then further reviewed and filtered and secondary
references found. Here we review the different types of abnormal movements reported with anatomical correlation, epidemiology,
treatment and prognosis. Post stroke movement disorders can present acutely or as a delayed sequel. They can be hyperkinetic
(most commonly hemichorea-hemiballism) or hypokinetic (most commonly vascular parkinsonism). Most are caused by lesions in
the basal ganglia or thalamus but can occur with strokes at many different locations in the motor circuit. Many are self limiting
but treatment may be required for symptom control.
A 36 year old man, who sustained a skull fracture in 1984, was unconscious for 24 hours, and developed signs of Parkinson's syndrome 6 weeks after the injury. When assessed in 1995, neuroimaging disclosed a cerebral infarction due to trauma involving the left caudate and lenticular nucleus. Parkinson's syndrome was predominantly right sided, slowly progressive, and unresponsive to levodopa therapy. Reaction time tests showed slowness of movement initiation and execution with both hands, particularly the right. Recording of movement related cortical potentials suggested bilateral deficits in movement preparation. Neuropsychological assessment disclosed no evidence of major deficits on tests assessing executive function or working memory, with the exception of selective impairments on the Stroop and on a test of self ordered random number sequences. There was evidence of abulia. The results are discussed in relation to previous literature on basal ganglia lesions and the effects of damage to different points of the frontostriatal circuits.
Significance
Cases like that of Charles Whitman, who murdered 16 people after growth of a brain tumor, have sparked debate about why some brain lesions, but not others, might lead to criminal behavior. Here we systematically characterize such lesions and compare them with lesions that cause other symptoms. We find that lesions in multiple different brain areas are associated with criminal behavior. However, these lesions all fall within a unique functionally connected brain network involved in moral decision making. Furthermore, connectivity to competing brain networks predicts the abnormal moral decisions observed in these patients. These results provide insight into why some brain lesions, but not others, might predispose to criminal behavior, with potential neuroscience, medical, and legal implications.
Neuroscience has a long history of inferring brain function by examining the relationship between brain injury and subsequent behavioral impairments. The primary advantage of this method over correlative methods is that it can tell us if a certain brain region is necessary for a given cognitive function. In addition, lesion-based analyses provide unique insights into clinical deficits. In the last decade, statistical voxel-based lesion behavior mapping (VLBM) emerged as a powerful method for understanding the architecture of the human brain. This review illustrates how VLBM improves our knowledge of functional brain architecture, as well as how it is inherently limited by its mass-univariate approach. A wide array of recently developed methods appear to supplement traditional VLBM. This paper provides an overview of these new methods, including the use of specialized imaging modalities, the combination of structural imaging with normative connectome data, as well as multivariate analyses of structural imaging data. We see these new methods as complementing rather than replacing traditional VLBM, providing synergistic tools to answer related questions. Finally, we discuss the potential for these methods to become established in cognitive neuroscience and in clinical applications.
Objective: The benefit of deep brain stimulation (DBS) for Parkinson's disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remains unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort.
Methods: A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of Unified Parkinson's Disease Rating Scale). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center.
Results: In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p < 0.001). This same connectivity profile predicted response in an independent patient cohort (p < 0.01). Structural and functional connectivity were independent predictors of clinical improvement (p < 0.001) and estimated response in individual patients with an average error of 15% UPDRS improvement. Results were similar using connectome data from normal subjects or a connectome age, sex, and disease-matched to our DBS patients.
Interpretation: Effective STN-DBS for PD is associated with a specific connectivity profile that can predict clinical outcome across independent cohorts. This prediction does not require specialized imaging in PD patients themselves. This article is protected by copyright. All rights reserved.
Three-dimensional atlases of subcortical brain structures are valuable tools to reference anatomy in neuroscience and neurology. For instance, they can be used to study the position and shape of the three most common deep brain stimulation (DBS) targets, the sub-thalamic nucleus (STN), internal part of the pallidum (GPi) and ventral intermediate nucleus of the thalamus (VIM) in stereotactic space and in spatial relationship to DBS electrodes. Here, we present a composite atlas that is based on manual segmentations of a multimodal high resolution brain template, histology and structural connectivity. In a first step, four key structures were defined on the template itself using a combination of multi-spectral image analysis and manual segmentation. Second, these structures were used as anchor points to coregister a detailed histological atlas into standard space. Results show that this approach significantly improved coregistration accuracy over previously published methods. Finally, a sub-segmentation of STN and GPi into functional zones was achieved based on structural connectivity. The result is a composite atlas that defines key nuclei on the template itself, fills the gaps between them using histology and further subdivides them using structural connectivity. We show that the atlas can be used to segment DBS targets in single subjects, yielding more accurate results compared to priorly published atlases. The atlas will be made publicly available and constitutes a resource to study DBS electrode localizations in combination with modern neuroimaging methods.
Functional MRI has proven to be effective in detecting neural activity in brain cortices on the basis of blood oxygenation level dependent (BOLD) contrast, but has relatively poor sensitivity for detecting neural activity in white matter. To demonstrate that BOLD signals in white matter are detectable and contain information on neural activity, we stimulated the somatosensory system and examined distributions of BOLD signals in related white matter pathways. The temporal correlation profiles and frequency contents of BOLD signals were compared between stimulation and resting conditions, and between relevant white matter fibers and background regions, as well as between left and right side stimulations. Quantitative analyses show that, overall, MR signals from white matter fiber bundles in the somatosensory system exhibited significantly greater temporal correlations with the primary sensory cortex and greater signal power during tactile stimulations than in a resting state, and were stronger than corresponding measurements for background white matter both during stimulations and in a resting state. The temporal correlation and signal power under stimulation were found to be twice those observed from the same bundle in a resting state, and bore clear relations with the side of stimuli. These indicate that BOLD signals in white matter fibers encode neural activity related to their functional roles connecting cortical volumes, which are detectable with appropriate methods.
Intracellular α-synuclein (α-syn)-rich protein aggregates called Lewy pathology (LP) and neuronal death are commonly found in the brains of patients with clinical Parkinson disease (cPD). It is widely believed that LP appears early in the disease and spreads in synaptically coupled brain networks, driving neuronal dysfunction and death. However, post-mortem analysis of human brains and connectome-mapping studies show that the pattern of LP in cPD is not consistent with this simple model, arguing that, if LP propagates in cPD, it must be gated by cell- or region-autonomous mechanisms. Moreover, the correlation between LP and neuronal death is weak. In this Review, we briefly discuss the evidence for and against the spreading LP model, as well as evidence that cell-autonomous factors govern both α-syn pathology and neuronal death.
Parkinsonism associated with strategic infarcts involving Substantia Nigra is extremely rare. We herein report a case of bilateral parkinsonism related to midbrain lesion secondary to Percheron Artery occlusion. This case report supports the hypothesis about the relationship between strategic vascular lesions and the subsequent development of parkinsonism.
Focal brain injury can sometimes lead to bizarre symptoms, such as the delusion that a family member has been replaced by an imposter (Capgras syndrome). How a single brain lesion could cause such a complex disorder is unclear, leading many to speculate that concurrent delirium, psychiatric disease, dementia, or a second lesion is required. Here we instead propose that Capgras and other delusional misidentification syndromes arise from single lesions at unique locations within the human brain connectome. This hypothesis is motivated by evidence that symptoms emerge from sites functionally connected to a lesion location, not just the lesion location itself. First, 17 cases of lesion-induced delusional misidentifications were identified and lesion locations were mapped to a common brain atlas. Second, lesion network mapping was used to identify brain regions functionally connected to the lesion locations. Third, regions involved in familiarity perception and belief evaluation, two processes thought to be abnormal in delusional misidentifications, were identified using meta-analyses of previous functional magnetic resonance imaging studies. We found that all 17 lesion locations were functionally connected to the left retrosplenial cortex, the region most activated in functional magnetic resonance imaging studies of familiarity. Similarly, 16 of 17 lesion locations were functionally connected to the right frontal cortex, the region most activated in functional magnetic resonance imaging studies of expectation violation, a component of belief evaluation. This connectivity pattern was highly specific for delusional misidentifications compared to four other lesion-induced neurological syndromes (P < 0.0001). Finally, 15 lesions causing other types of delusions were connected to expectation violation (P < 0.0001) but not familiarity regions, demonstrating specificity for delusion content. Our results provide potential neuroanatomical correlates for impaired familiarity perception and belief evaluation in patients with delusional misidentifications. More generally, we demonstrate a mechanism by which a single lesion can cause a complex neuropsychiatric syndrome based on that lesion's unique pattern of functional connectivity, without the need for pre-existing or hidden pathology.
Objective:
Freezing of gait is a disabling symptom in Parkinson's disease and related disorders, but the brain regions involved in symptom generation remain unclear. Here we analyze brain lesions causing acute onset freezing of gait to identify regions causally involved in symptom generation.
Methods:
Fourteen cases of lesion-induced freezing of gait were identified from the literature and lesions were mapped to a common brain atlas. Because lesion-induced symptoms can come from sites connected to the lesion location, not just the lesion location itself, we also identified brain regions functionally connected to each lesion location. This technique, termed lesion network mapping, has been recently shown to identify regions involved in symptom generation across a variety of lesion-induced disorders.
Results:
Lesion location was heterogeneous and no single region could be considered necessary for symptom generation. However, over 90% (13/14) of lesions were functionally connected to a focal area in the dorsal medial cerebellum. This cerebellar area overlapped previously recognized regions that are activated by locomotor tasks, termed the cerebellar locomotor region. Connectivity to this region was specific to lesions causing freezing of gait compared to lesions causing other movement disorders (hemichorea or asterixis).
Interpretation:
Lesions causing freezing of gait are located within a common functional network characterized by connectivity to the cerebellar locomotor region. These results based on causal brain lesions complement prior neuroimaging studies in Parkinson's disease patients, advancing our understanding of the brain regions involved in freezing of gait. This article is protected by copyright. All rights reserved.
Objective:
To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network.
Methods:
We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness.
Results:
A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks.
Conclusions:
Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.
In the human brain, the claustrum is a small subcortical telencephalic nucleus, situated between the insular cortex and the putamen. A plethora of neuroanatomical studies have shown the existence of dense, widespread, bidirectional and bilateral monosynaptic interconnections between the claustrum and most cortical areas. A rapidly growing body of experimental evidence points to the integrative role of claustrum in complex brain functions, from motor to cognitive. Here, we examined for the first time, the behaviour of the classical monoamine neurotransmitters dopamine, noradrenaline and serotonin in the claustrum of the normal autopsied human brain and of patients who died with idiopathic Parkinson's disease (PD). We found in the normal claustrum substantial amounts of all three monoamine neurotransmitters, substantiating the existence of the respective brain stem afferents to the claustrum. In PD, the levels of dopamine and noradrenaline were greatly reduced by 93% and 81%, respectively. Serotonin levels remained unchanged. We propose that by virtue of their projections to the claustrum, the brain stem dopamine, noradrenaline and serotonin systems interact directly with the cortico-claustro-cortical information processing mechanisms, by-passing their (parallel) routes via the basal ganglia-thalamo-cortical circuits. We propose that loss of dopamine and noradrenaline in the PD claustrum is critical in the aetiology of both the motor and the non-motor symptoms of PD. This article is protected by copyright. All rights reserved.
Objective:
To determine whether neuroanatomically heterogeneous strokes causing hemichorea-hemiballismus localize to a common functional network.
Methods:
We identified 29 cases of lesion-induced hemichorea-hemiballismus from the literature and mapped each lesion volume onto a reference brain. Using a recently validated technique termed lesion network mapping, we tested whether these lesions belonged to the same functional network. To accomplish this, the network of brain regions functionally connected to each lesion was identified using a connectome dataset from healthy participants. Network maps were overlapped to identify any region functionally connected to our set of lesions. Specificity was evaluated using a case-control design; control cohorts included a group of similar lesions randomized to different brain locations and a second group of lesions causing a separate movement disorder, asterixis. Reproducibility was evaluated using an independent cohort of 10 additional hemichorea-hemiballismus cases.
Results:
Lesions showed heterogeneity in anatomical location, consistent with prior reports. However, at least 90% of these lesions showed network overlap in the posterolateral putamen. This result was specific to lesions causing hemichorea-hemiballismus and reproducible in an independent cohort. The putaminal overlap site was itself connected to a broader motor network that predicted the distribution of lesions causing hemichorea-hemiballismus.
Conclusions:
Strokes causing hemichorea-hemiballismus, while anatomically heterogeneous, localize to a common functional network. Specifically, lesions occur in regions functionally connected to the posterolateral putamen, a region previously implicated in hyperkinetic movement disorders. Lesion network mapping may be useful in identifying the neuroanatomical substrates of heterogeneous lesion-based disorders.
Studies of patients with brain damage have highlighted a broad neural network of limbic and prefrontal areas as important for adaptive decision-making. However, some patients with damage outside these regions have impaired decision-making behavior, and the behavioral impairments observed in these cases are often attributed to the general variability in behavior following brain damage, rather than a deficit in a specific brain-behavior relationship. A novel approach, lesion-derived network mapping, uses healthy subject resting-state functional connectivity (RSFC) data to infer the areas that would be connected with each patient's lesion area in healthy adults. Here, we used this approach to investigate whether there was a systematic pattern of connectivity associated with decision-making performance in patients with focal damage in areas not classically associated with decision-making. These patients were categorized a priori into "impaired" or "unimpaired" groups based on their performance on the Iowa Gambling Task (IGT). Lesion-derived network maps based on the impaired patients showed overlap in somatosensory, motor and insula cortices, to a greater extent than patients who showed unimpaired IGT performance. Akin to the classic concept of "diaschisis" (von Monakow, 1914), this focus on the remote effects that focal damage can have on large-scale distributed brain networks has the potential to inform not only differences in decision-making behavior, but also other cognitive functions or neurological syndromes where a distinct phenotype has eluded neuroanatomical classification and brain-behavior relationships appear highly heterogeneous.
There are different etiologies of hemiparkinsonism. A few patients with hemiparkinsonism secondary to infarction in the contralateral substantia nigra have been reported in the literature, and only one of these patients presented with pure hemiparkinsonism. This paper reports the unusual case of a patient presenting with pure hemiparkinsonism secondary to a lacunar stroke in the substania nigra. A 66-year-old man who presented with a 5-year history of left-sided hemiparkinsonism manifested by tremor, rigidity, and bradykinesia located mainly on the upper extremity. Magnetic resonance imaging of the brain revealed a lacunar infarct located in the right substantia nigra. Patients experiencing sudden hemiparkinsonism should be investigated to rule out any abnormality in the contralateral substantia nigra. This case points to the significance of neuroimaging in the evaluation of unilateral parkinsonism.
Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease.
Copyright © 2015 Elsevier Ltd. All rights reserved.
The basal ganglia were originally thought to be associated purely with motor control. However, dysfunction and pathology of different regions and circuits are now known to give rise to many clinical manifestations beyond the association of basal ganglia dysfunction with movement disorders. Moreover, disorders that were thought to be caused by dysfunction of the basal ganglia only, such as Parkinson's disease and Huntington's disease, have diverse abnormalities distributed not only in the brain but also in the peripheral and autonomic nervous systems; this knowledge poses new questions and challenges. We discuss advances and the unanswered questions, and ways in which progress might be made.
Magnetic resonance (MR) and 11C-N-methylspiperone (11C-NMSP)/positron emission tomography (PET) imagings were repeatedly performed in a 50-year-old man with the interval form of carbon monoxide (CO) poisoning. In MR images obtained when delayed neuropsychiatric symptoms developed (two months after poisoning), the inner segments of the bilateral globus pallidus appeared as high signal intensities in the T1-weighted and low signal intensities in the T2-weighted images, suggesting prior focal hemorrhage in these areas. A PET study with 11C-NMSP performed at that time showed an increase in dopamine D2 receptor binding in the caudate and putamen. Treatment with bromocriptine was very effective and five months after the poisoning, MR and 11C-NMSP/PET images showed improvement, concomitantly with the disappearance of the neuropsychiatric symptoms.
Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein α-synuclein or the microtubule binding protein tau. In idiopathic Parkinson's disease (PD), α-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major α-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of α-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, α-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.
Statistical parametric maps are spatially extended statistical processes that are used to test hypotheses about regionally specific effects in neuroimaging data. The most established sorts of statistical parametric maps (e.g., Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699; Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) are based on linear models, for example ANCOVA, correlation coefficients and t tests. In the sense that these examples are all special cases of the general linear model it should be possible to implement them (and many others) within a unified framework. We present here a general approach that accomodates most forms of experimental layout and ensuing analysis (designed experiments with fixed effects for factors, covariates and interaction of factors). This approach brings together two well established bodies of theory (the general linear model and the theory of Gaussian fields) to provide a complete and simple framework for the analysis of imaging data.
The importance of this framework is twofold: (i) Conceptual and mathematical simplicity, in that the same small number of operational equations is used irrespective of the complexity of the experiment or nature of the statistical model and (ii) the generality of the framework provides for great latitude in experimental design and analysis.
Transcranial magnetic stimulation (TMS) to the left dorsolateral prefrontal cortex (DLPFC) is used clinically for the treatment of depression. However, the antidepressant mechanism remains unknown and its therapeutic efficacy remains limited. Recent data suggest that some left DLPFC targets are more effective than others; however, the reasons for this heterogeneity and how to capitalize on this information remain unclear.
Intrinsic (resting state) functional magnetic resonance imaging data from 98 normal subjects were used to compute functional connectivity with various left DLPFC TMS targets employed in the literature. Differences in functional connectivity related to differences in previously reported clinical efficacy were identified. This information was translated into a connectivity-based targeting strategy to identify optimized left DLPFC TMS coordinates. Results in normal subjects were tested for reproducibility in an independent cohort of 13 patients with depression.
Differences in functional connectivity were related to previously reported differences in clinical efficacy across a distributed set of cortical and limbic regions. Dorsolateral prefrontal cortex TMS sites with better clinical efficacy were more negatively correlated (anticorrelated) with the subgenual cingulate. Optimum connectivity-based stimulation coordinates were identified in Brodmann area 46. Results were reproducible in patients with depression.
Reported antidepressant efficacy of different left DLPFC TMS sites is related to the anticorrelation of each site with the subgenual cingulate, potentially lending insight into the antidepressant mechanism of TMS and suggesting a role for intrinsically anticorrelated networks in depression. These results can be translated into a connectivity-based targeting strategy for focal brain stimulation that might be used to optimize clinical response.
FSL (the FMRIB Software Library) is a comprehensive library of analysis tools for functional, structural and diffusion MRI brain imaging data, written mainly by members of the Analysis Group, FMRIB, Oxford. For this NeuroImage special issue on "20 years of fMRI" we have been asked to write about the history, developments and current status of FSL. We also include some descriptions of parts of FSL that are not well covered in the existing literature. We hope that some of this content might be of interest to users of FSL, and also maybe to new research groups considering creating, releasing and supporting new software packages for brain image analysis.
Network analysis of functional brain imaging data is an innovative approach to study circuit abnormalities in neurodegenerative diseases. In Parkinson's disease, spatial covariance analysis of resting-state metabolic images has identified specific regional patterns associated with motor and cognitive symptoms. With functional imaging, these metabolic networks have recently been used to measure system-related progression and to evaluate novel treatment strategies. Network analysis is also being used to characterize specific functional biomarkers for Huntington's disease and Alzheimer's disease. These networks have been particularly helpful in uncovering compensatory mechanisms in genetically at-risk individuals. Ongoing developments in network applications are likely to enhance the role of functional imaging in the investigation of neurodegenerative disorders.
Cavernous angiomas of the upper brainstem causing hemiparkinsonism are very rare. Due to their difficult-to-reach localization, brainstem cavernomas, in particular those in anterior locations, continue to present a therapeutic challenge.
The authors report on a 16-year-old boy with a pontomesencephalic cavernoma who developed hemiparkinsonism and hemiparesis after hemorrhage. After complete surgical removal of the pontomesencephalic cavernoma via a pterional transsylvian approach, his symptoms resolved.
Although pontomesencephalic cavernomas occupying the ventral portion of the brainstem are regarded as problematic for resection, the pterional transsylvian approach provides an excellent route for removal of cavernomas that are in contact with the ventral surface of the midbrain in the interpeduncular cistern. Surgical removal of this type of lesion is recommended because resolution of clinical symptoms, including hemiparkinsonism, can be achieved.
A 21-year-old woman, who experienced manual strangulation, developed delayed parkinsonism associated with a selective symmetric basal ganglia lesion. The patient had recovered completely one year after early combination therapy. This case emphasizes the need for greater attention in detecting early brain injuries in those afflicted with strangulation so as to provide optimal management.
One hundred MRI examinations of normal subjects obtained at 0.5 T were studied in an effort to evaluate the claustrum and to establish a control group for patients with Wilson's disease. The claustrum was detectable unilaterally or bilaterally in 40 out of 100 subjects (40%) on spin-echo long TR (proton density and T2-weighted) MR images as a thin sheet of grey matter enclosed by low signal white matter of the external and extreme capsules. Spin-echo T1-weighted images were negative for the claustrum, however, it was identifiable in 12 out of 25 subjects (48%) studied utilizing the inversion recovery pulse sequence. In addition, eight patients with clinically established diagnoses of Wilson's disease were evaluated. The claustrum was normal (invisible) in four neurologically asymptomatic Wilson's disease patients, however, in 75% (n = 3) of the four neurologically symptomatic patients it was bilaterally thickened and bright on long-TR MR images. The bright claustrum appears to be a new sign in Wilson's disease.
We report a patient with right hemiparkinsonism following haemorrhage in the left substantia nigra. The hemiparkinsonism responded to treatment with trihexyphenidyl hydrochloride and deteriorated after temporary discontinuation of the drug. Single photon emission computed tomography using technetium 99m d, l-hexamethylpropyleneamine oxide showed reduced uptake in the left putamen, globus pallidus and thalamus.