key: cord-0028131-m22h18wc
authors: Jang, Sung Ho; Byun, Dong Hyun
title: A Review of Studies on the Role of Diffusion Tensor Magnetic Resonance Imaging Tractography in the Evaluation of the Fronto-Subcortical Circuit in Patients with Akinetic Mutism
date: 2022-02-19
journal: Med Sci Monit
DOI: 10.12659/msm.936251
sha: c6342ad92e6fcf14183102e0ab680ac461da6aa2
doc_id: 28131
cord_uid: m22h18wc

Akinetic mutism (AM) is characterized by the complete absence of spontaneous behavior (akinesia) and speech (mutism) with the preservation of executive functions for movements and speaking. Elucidation of the pathophysiological mechanisms or neural correlates for AM is clinically important because patients can recover from AM after medication and neuromodulation. The fronto-subcortical circuit is a critically important neural structure in the pathophysiology of AM. Using diffusion tensor tractography, a few neural tracts in the fronto-subcortical circuit can be reconstructed. This mini-review article evaluated 6 DTT-based studies on the fronto-subcortical circuit injury in patients with AM. According to these results, the neural tracts among the fronto-subcortical circuit, which are related to AM, were as follows (in decreasing order of importance): 1) the prefronto-caudate tract, 2) the prefronto-thalamic tract, and 3) the cingulum. In particular, the medial prefrontal cortex is an important brain area related to recovery from AM. However, only 6 studies on this topic have been published, and most were case reports. In addition, these studies analyzed only a few neural tracts in the fronto-subcortical circuit. Because AM is a rare disorder, studies involving a large number of subjects might be impossible. Nevertheless, an analysis of various neural tracts in the fronto-subcortical circuit is necessary. For this, reconstruction of the other neural tracts in the fronto-subcortical circuit should be performed first. This review aims to present the findings from recent studies on the role of DTT in evaluation of fronto-subcortical circuit injury in patients with AK.

Akinetic mutism (AM) is the most severe disorder among the 3 disorders of diminished motivation (AM, abulia, and apathy) [1] . AM is characterized by the complete absence of spontaneous behavior (akinesia) and speech (mutism) with the preservation of executive functions for movements and speaking [1] [2] [3] . AM is clinically important because it causes in ability to perform activities of daily living and imposes a heavy burden on caregivers [1, 4, 5] . Elucidation of pathophysiological mechanism or neural correlates for AM is clinically important because patients can recover from AM after receiving medication, such as dopamine agonists and brain stimulants [1, 3] . In addition, recently developed neuro-stimulation techniques, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, can be applied to the neural correlates for AM recovery [1, 3, 6] . However, the pathophysiological mechanism of AM is not completely understood.

The fronto-subcortical circuit (frontal lobe and its subcortical connections) is a critically important neural structure in the pathophysiology of AM [1, 3, [7] [8] [9] . Specifically, injury to the cortico-striatal-pallidal-thalamic circuit has been suggested to be the most plausible pathophysiological mechanism of AM [1, 3, 7] . The reconstruction of various neural tracts in the fronto-subcortical circuit is essential for elucidating the pathophysiological mechanism of AM. However, precise reconstruction of the fronto-subcortical circuit in a live human brain has been impossible. Since Cairns et al reported the first case of AM in 1941, many studies have reported the neural correlates for AM as the following specific neuropathological brain regions, which were commonly associated with bilateral hemispheric pathologies, using conventional brain imaging or nuclear imaging: (1) the frontal lobe (the medial frontal cortex and anterior cingulate cortex), (2) basal ganglia (striatum and pallidum), (3) thalamus (anterior and medial nuclei), and (4) midbrain (ventral tegmental area) [3, [10] [11] [12] [13] [14] [15] [16] . AM can be classified into 2 subtypes according to the anatomical location of the brain lesions: (1) the frontal AM (hyperpathic), lesion in the frontal region; and (2) mesencephalic AM (somnolescent or hypopathic), lesions in the thalamus and midbrain [16] .

The diffusion tensor imaging (DTI), which generates images based on estimations of the diffusion of water molecules in various microstructures, has enabled evaluation of the entire microstructural features of the white matter [17, 18] . In particular, using diffusion tensor tractography (DTT) reconstructed based on DTI data, the neural tracts in a live human brain can be reconstructed three-dimensionally [19, 20] . The main advantage of DTT is that the entire neural tract can be evaluated in terms of the DTT parameters (fractional anisotropy, mean diffusivity, and tract volume) and configurational analysis (integrity and configuration) [2, [21] [22] [23] . Some neural tracts of the fronto-subcortical circuit, including the prefronto-caudate tract, prefronto-putaminal tract, prefronto-thalamic (mediodorsal nucleus) tracts, and cingulum, were reconstructed using DTT [2, [24] [25] [26] [27] . As a result, DTT has transformed research into AM from a brain lesion study to a fronto-subcortical circuit study. Based on the above studies, several papers have reported that AM is related to injuries of the above neural tracts [2, 21, 24, [28] [29] [30] .

In this study, we reviewed 6 DTT studies that demonstrated neural tract injury in patients with AM after a brain injury [2, 21, 24, [28] [29] [30] (Table 1) . This review aims to present the findings from recent studies on the role of DTT in evaluation of fronto-subcortical circuit injury in patients with AK.

Publication year

Pathology of brain injury 

In 2017, Jang and Kwon reported the case of a patient who showed AM with injuries and subsequent degeneration of the prefronto-caudate and the prefronto-thalamic tracts after a mild traumatic brain injury (TBI) [2] . A 20-year-old man had a mild TBI caused by a pedestrian-car accident. Since the onset of mild TBI, he revealed the clinical features of abulia (decreased activity and speech). His abulia aggravated to AM approximately 1 year after onset. He presented the typical clinical features of AM as follows. He remained lying down all day with no spontaneous movement or speech. Even during mealtime, he was fed by a caregiver and chewed according to the caregiver's order because he could not consume a meal or chew by himself [2] . On the 1-month DTT, the prefronto-caudate tract (the neural connectivity of the caudate nucleus to the medial prefrontal cortex) showed partial discontinuation in both hemispheres. These findings were aggravated on the 2-year DTT, indicating neural degeneration of injured prefronto-caudate tracts. However, the orbitofrontal-thalamic tract was thin in the left hemisphere on 1-month-DTT. In contrast, this tract became thinner in both hemispheres on the 2-year DTT, suggesting neural degeneration of the injured left orbitofrontal-thalamic tract. The authors concluded that followup DTTs demonstrated injuries to the prefronto-caudate tract and the orbitofrontal-thalamic tract and subsequent degeneration of these injured neural tracts concurrent with an aggravation of abulia to AM in this patient. This study showed that the aggravation of abulia to AM was concurrent with the degenerations of the injured prefronto-caudate and the orbitofrontal-thalamic tracts. However, the authors could not discern which neural tract -the injured prefronto-caudate tract or the orbitofrontal-thalamic tract -was responsible for his AM. Furthermore, the authors estimated the neural tracts only by configurational analysis without DTT parameter data. Another limitation of this study was that only 2 neural tracts (the prefronto-caudate and prefronto-thalamic tracts) were estimated among the many neural tracts in the fronto-subcortical tract. [1, 3] . During rehabilitation for 5 weeks, her AM improved gradually, and she could perform some activities of daily living (eg, eating, dressing, and walking). On 5-week DTT, the prefrontal-caudate tract revealed injury findings in both hemispheres (the neural connectivity of the caudate nucleus to the medial prefrontal cortex) (Broadmann area: 10 and 12), and the orbitofrontal cortex (Broadmann area 11 and 13) was decreased in both hemispheres [31] . On the 10-week DTT, however, partial recovery of the injured left prefronto-caudate tract was observed (the neural connectivity of the left caudate nucleus to the left medial prefrontal cortex was increased). The authors concluded that the recovery of the injured prefronto-caudate tract concurrent with the improvement of AK was demonstrated in this patient, using follow-up DTTs. The strength of this study is that it demonstrates the effects of dopaminergic drugs on AM and recovery of the injured prefronto-caudate tract [1, 3] . However, it suggested that the medical prefrontal cortex appears to be related more to AM than the orbitofrontal cortex because the neural connectivity to the medial prefrontal cortex was increased with the recovery of AM in this patient. On the other hand, this study analyzed only the prefronto-caudate tract among various neural tracts in the fronto-subcortical circuit. Moreover, this study provided only configurational data without DTT parameter data.

In 2017, Jang et al reported the case of a stroke patient who showed recoveries of AM and injured prefronto-caudate tract, which was related to relief of the hydrocephalus, using follow-up DTTs [28] . A 76-year-old female patient was diagnosed e936251-3 

with an aneurysmal subarachnoid hemorrhage caused by rupture of a right posterior communicating artery aneurysm. She underwent craniotomy and clipping of the aneurysmal neck. At 6 months after onset, when she started rehabilitation at another university hospital, she revealed the typical clinical features of AM (she did not move or speak spontaneously). Hydrocephalus was detected on the brain magnetic resonance images (Figure 1) . The patient received comprehensive rehabilitative management, including dopaminergic drugs to improve AM (pramipexole, amantadine, ropinirole, and levodopa) [1, 3] . Despite 2 months of rehabilitation, her AM did not improve significantly. Consequently, she received a ventriculoperitoneal shunt operation for hydrocephalus 8 months after onset. After the shunt operation, she remained in the AM state. Before her shunt operation, she underwent similar comprehensive rehabilitative management. During 1-month rehabilitation, her AM improved gradually; she could perform some daily living activities herself, including washing, eating, and dressing, 9 months after onset. In addition, she could speak with some fluency. The prefronto-caudate tract showed injury findings in both hemispheres on the 6-month DTT (the neural connectivity of the caudate nucleus to the medial prefrontal and orbitofrontal cortices was decreased in both hemispheres) (Figure 1) . By contrast, these injured prefronto-caudate tracts showed recovery on the 9-month DTT (the neural connectivity of the caudate nucleus to the medial prefrontal cortex was increased on both sides). The integrity of the arcuate fasciculus was preserved in both hemispheres on both 6-and 9-month DTTs. The authors concluded that this patient had recovered from AM and injured prefronto-caudate tracts. This study provides some take-home messages. First, the medial prefrontal cortex is more important for AM than the orbitofrontal cortex because this patient's AM recovered along with the increased neural connectivity to the medial prefrontal cortex. Second, although dopaminergic agonists are effective in the recovery of AM, relief of the hydrocephalus is more important when combined with AM. Third, this study presented the intact findings of AF in both hemispheres on both 6-and 10-month DTT, suggesting that the mutism in this patient occurred irrespective of the language ability. However, the study was limited because the prefrontal tract was analyzed in terms of configuration without DTT parameter data.

In 2018, Jang et al reported a patient who showed AM concurrent with severe injuries of both prefronto-caudate tracts due to an accident [29] . A 72-year-old man had head trauma resulting from an injury to his frontal area caused by an electric grinder while working at his home. He was diagnosed with a traumatic intracerebral hemorrhage in both frontal lobes, intraventricular hemorrhage, and subarachnoid hemorrhage and underwent hematoma removal and decompressive craniectomy. At 2 months after onset, when starting rehabilitation, he had the typical clinical features of AM; he remained lying down all day, with no spontaneous movement and speech. At 2 months after onset, brain magnetic resonance images showed leukomalactic lesions in both prefrontal areas, including both cingulate gyri. The 2-month DTT revealed a severe injury of the prefronto-caudate tract in both sides (decreased neural connectivity of the caudate nucleus to the medial prefrontal and orbitofrontal cortices). Hence, injuries of both prefronto-caudate tracts were observed in this patient who developed AM following TBI. The authors suggested that injury of the prefronto-caudate tract might be a pathophysiological mechanism of AM in patients with brain injury. However, only the prefrontocaudate tract was analyzed: even the anterior cingulum, which appeared to be injured severely in both sides on brain magnetic resonance images, was not analyzed.

Recently (2022), Byun and Jang reported the case of a patient in whom a differential diagnosis of AM with a disorder of consciousness was made using DTT [30] . A 69-year-old female patient was diagnosed with a subarachnoid hemorrhage, intraventricular hemorrhage, and an intracerebral hemorrhage produced by the subarachnoid hemorrhage. She exhibited impaired consciousness with a Coma Recovery Scale-Revised score of 13 until 1 month after onset. Her impaired consciousness slowly recovered to a normal state according to the Coma Recovery Scale-Revised (23 points: full score) at 7 weeks after onset, but she showed the typical clinical features of AM (no spontaneous movement or speech). On the DTT performed at 1 month, the upper and lower dorsal ascending reticular activating systems, which are related to a disorder of consciousness, showed an almost normal state. In contrast, the prefronto-caudate and prefronto-thalamic tracts, which are related to AM, showed severe injuries. These DTT results suggested that the patient's main clinical features were not a disorder of consciousness, but AM. The authors concluded that DTT for the ascending reticular activating system and the prefronto-caudate and prefronto-thalamic tracts could provide additional evidence for a differential diagnosis of disorders of consciousness and AM at the early stages of stroke.

This mini-review article evaluated 6 DTT-based studies on fronto-subcortical circuit injury in patients with AM and the pathophysiological mechanisms involved [2, 21, 24, [28] [29] [30] . The information provided in these reviewed studies suggests that DTT could be helpful for elucidating the pathophysiological mechanism of AM. According to the results of these studies, the neural tracts among the fronto-subcortical circuit, which were related to AM, are as follows in decreasing order: (1) prefronto-caudate tract, (2) prefronto-thalamic tract, and (3) cingulum [2, 21, 24, [28] [29] [30] . In particular, the medial prefrontal cortex was suggested as an important brain area for the recovery e936251-5 of AM [21, 28] . These studies could facilitate the neurorehabilitation of patients with AM [6] . Only 6 studies on this topic have been published; most were case reports. In addition, these studies analyzed only a few neural tracts in the frontosubcortical circuit. Studies involving a large number of subjects might be impossible because AM is a rare disorder, but analysis of various neural tracts in the fronto-subcortical circuit is needed. For this, use of the reconstruction methods for the other neural tracts in the fronto-subcortical circuit should be encouraged. In addition, a precise three-dimensional reconstruction method for the prefronto-caudate tract and the prefronto-striatal tract, which were reported the neural connectivity from 1 region of interest, is needed [21, 25, 28, 29] .

On the other hand, all 6 reviewed studies corresponded to the frontal AM. Further studies on mesencephalic AM based on DTI or DTT are needed.

This review presented the findings from the only 6 identified main studies on the role of DTT in evaluation of fronto-subcortical circuit injury in patients with AK. Although this in vivo imaging method shows promise for evaluating the fronto-subcortical circuit in stroke, TBI, and brain tumors, further studies are required to evaluate the role of DTT in other brain pathologies with AK. Figure 1 , is reproduced here with permission.

Disorders of diminished motivation

Akinetic mutism in a patient with mild traumatic brain injury: A diffusion tensor tractography study

On the pathophysiology and treatment of akinetic mutism

Neural correlates for apathy: Frontal-prefrontal and parietal cortical-subcortical circuits

Akinetic mutism and coronavirus disease 2019: A narrative review

Akinetic mutism reversed by inferior parietal lobule repetitive theta burst stimulation: Can we restore default mode network function for therapeutic benefit?

Akinetic mutism. disconnection of frontal-subcortical circuits

The human frontal lobes: Functions and disorders. 3 rd ed

The role of the medial prefrontal cortex in cognition, ageing and dementia

Akinetic mutism with an epidermoid cyst of the 3 rd ventricle

Diminution of basal ganglia dopaminergic function may play an important role in the generation of akinetic mutism in a patient with anterior cerebral arterial infarct

Persistent akinetic mutism after bilateral paramedian thalamic infarction

Akinetic mutism following stroke

Subarachnoid haemorrhage and akinetic mutism

Full recovery of akinetic mutism after corpus callosum infarction in post subarachnoid hemorrhage of ruptured distal anterior cerebral artery aneurysm

Akinetic mutism and mixed transcortical aphasia following left thalamo-mesencephalic infarction

Diffusion tensor imaging (DTI)-based white matter mapping in brain research: A review

Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI

Functional role of the corticoreticular pathway in chronic stroke patients

Topography of connections between human prefrontal cortex and mediodorsal thalamus studied with diffusion tractography

Recovery of an injured prefronto-caudate tract in a patient with traumatic brain injury: A diffusion tensor tractography study

Diagnostic sensitivity of traumatic axonal injury of the spinothalamic tract in patients with mild traumatic brain injury

Relationship between dizziness and the core vestibular projection injury in patients with mild traumatic brain injury

A method for safely resecting anterior butterfly gliomas: The surgical anatomy of the default mode network and the relevance of its preservation

Fronto-striatal connections in the human brain: A probabilistic diffusion tractography study

Probabilistic diffusion tractography with multiple fibre orientations: What can we gain?

Thalamocortical connections between the mediodorsal nucleus of the thalamus and prefrontal cortex in the human brain: A diffusion tensor tractographic study

Recovery of akinetic mutism and injured prefronto-caudate tract following shunt operation for hydrocephalus and rehabilitation: A case report

Akinetic mutism following prefrontal injury by an electrical grinder a case report: A diffusion tensor tractography study

Differential diagnosis of akinetic mutism and disorder of consciousness using diffusion tensor tractography. Front Hum Neurosci

Brodmann's localization in the cerebral cortex: the principles of comparative localisation in the cerebral cortex based on cytoarchitectonics